Anti-CSF1R Antibodies for Treating PVNS

ABSTRACT

Methods of treating pigmented villonodular synovitis (PVNS) with antibodies that bind colony stimulating factor 1 receptor (CSF1R) are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/015,371, filed Jun. 22, 2018, which is a continuation ofU.S. patent application Ser. No. 14/976,346, filed Dec. 21, 2015, nowU.S. Pat. No. 10,040,858 issued Aug. 7, 2018, which claims the benefitof priority of US Provisional Application Nos. 62/095,297, filed Dec.22, 2014, and 62/163,251, filed May 18, 2015, both of which areincorporated by reference herein in their entirety for any purpose.

SEQUENCE LISTING

The present application is filed with a Sequence Listing in electronicformat. The Sequence Listing is provided as a file entitled“2015-12-08_01134-0037 00PCT_SeqList_ST25.txt” created on Dec. 8, 2015,which is 146,937 bytes in size. The information in the electronic formatof the sequence listing is incorporated herein by reference in itsentirety.

TECHNICAL FIELD

Methods of treating pigmented villonodular synovitis (PVNS) withantibodies that bind colony stimulating factor 1 receptor (CSF1R) areprovided.

BACKGROUND

Colony stimulating factor 1 receptor (referred to herein as CSF1R; alsoreferred to in the art as FMS, FIM2, C-FMS, M-CSF receptor, and CDl15)is a single-pass transmembrane receptor with an N-terminal extracellulardomain (ECD) and a C-terminal intracellular domain with tyrosine kinaseactivity. Ligand binding of CSF1 or the interleukin 34 ligand (referredto herein as IL-34; Lin et al., Science 320: 807-11 (2008)) to CSF1Rleads to receptor dimerization, upregulation of CSF1R protein tyrosinekinase activity, phosphorylation of CSF1R tyrosine residues, anddownstream signaling events. CSF1R activation by CSF1 or IL-34 leads tothe trafficking, survival, proliferation, and differentiation ofmonocytes and macrophages, as well as other monocytic cell lineages suchas osteoclasts, dendritic cells, and microglia.

Pigmented villonodular synovitis (PVNS) is a solid tumor of the synoviumwith features of both reactive inflammation and clonal neoplasticproliferation in which colony stimulating factor-1 (CSF1) is overexpressed. A common translocation of the CSF1 gene (1p13) to the COL6A3promoter (2q35) is present in approximately 60% of PVNS patients. Thetranslocation is accompanied by CSF1 overexpression in the synovium. Inaddition, approximately 40% of PVNS patients have CSF1 overexpression inthe absence of an identified CSF1 translocation. The consistent presenceof CSF1 overexpression in all cases of PVNS and reactive synovitissuggests both an important role for CSF1 in the spectrum of synovialpathologies and the utility of targeting the CSF1/CSF1R interactiontherapeutically. See West et al., 2006, Proc. Natl. Acad. Sci USA, 103:690-695.

In PVNS, CSF1 overexpression is present in a minority of synovial cells,whereas the majority of the cellular infiltrate expresses CSF1R but notCSF1. This has been characterized as a tumor-landscaping effect withaberrant CSF1 expression in the tumor cells, leading to the abnormalaccumulation of non-neoplastic cells that form a mass.

Surgery is the treatment of choice for patients with localized PVNS.Recurrences occur in 8-20% of patients and are often managed byre-excision. Diffuse tenosynovial giant cell tumor (TGCT/PVNS orPVNS/dtTGCT) tends to recur more often (33-50%) and has a much moreaggressive clinical course. Patients are often symptomatic and requiremultiple surgical procedures during their lifetime. For patients withunresectable disease or multiple recurrences, systemic therapy usingCSF1R inhibitors may help delay or avoid surgical procedures and improvefunctional outcomes. See Ravi et al., 2011, Am. J. Pathol., 179:240-247.

Imatinib, a non-specific inhibitor of CSF1R, has undergone evaluation inPVNS patients. Twenty-nine patients from 12 institutions in Europe,Australia, and the United States were included. The median age was 41years and the most common site of disease was the knee (n=17; 59%). Twopatients had metastatic disease to the lung and/or bone. Five of 27evaluable patients had complete (n=1) or partial (n=4) responses perRECIST for an overall response rate of 19%. Twenty of 27 patients (74%)had stable disease. Symptomatic improvement was noted in 16 of 22patients (73%) who were assessable for symptoms. Despite a high rate ofsymptomatic improvement and an overall favorable safety profile, 10patients discontinued treatment for toxicity or other reasons.

Alternative, less toxic treatments for PVNS are needed.

SUMMARY

In some embodiments, methods of treating a proliferative disorderinvolving a synovial joint and/or tendon sheath in a subject areprovided, comprising administering to the subject an effective amount ofan antibody that binds CSF1R. In some embodiments, the proliferativedisorder is selected from pigmented villonodular synovitis (PVNS), giantcell tumor of the tendon sheath (GCTTS), and tenosynovial giant celltumor (TGCT) such as diffuse type tenosynovial gian cell tumor (dtTGCT).In some embodiments, the disorder is pigmented villonodularsynovitis/diffuse type tenosynovial gian cell tumor (PVNS/dtTGCT). Insome embodiments, methods of treating pigmented villonodular synovitis(PVNS) in a subject are provided, comprising administering to thesubject an effective amount of an antibody that binds CSF1R.

In some embodiments, the antibody is administered once per week, onceper two weeks, once per three weeks, or once per month. In someembodiments, the antibody is administered at a dose of at least 1, atleast 2, at least 3, at least 4, at least 5, at least 6, at least 7, atleast 8, at least 10, at least 12, at least 15, at least 16, at least20, at least 30, at least 40, at least 50, or at least 100 mg/kg. Insome embodiments, the antibody is administered at a dose of 1, 2, 3, or4 mg/kg.

In some embodiments, the PVNS tumor volume is reduced by at least 30% orat least 40% or at least 50% or at least 60% or at least 70% afteradministration of at least two, at least three, at least four, at leastfive, at least six, at least seven, at least eight, at least nine, or atleast ten doses of the antibody that binds CSF1R. In some embodiments,the tumor volume is tumor volume in a single joint. In some embodiments,the single join is selected from a hip joint and a knee joint. In someembodiments, the tumor volume is total tumor volume in all jointsaffected by PVNS. In some embodiments, the subject experiences one ormore than one of the following improvements in symptoms: (a) a reductionin joint pain, (b) an increase range of motion in a joint, and (c) anincrease in functional capacity of a joint, following at least one doseof the antibody.

In some embodiments, prior to administering the first dose of theantibody, the subject received a first therapy selected from surgicalsynovectomy, radiation beam therapy, radio isotope synovectomy, andjoint replacement. In some embodiments, the PVNS recurred or progressedafter the first therapy. In some embodiments, the antibody isadministered prior to a therapy selected from surgical synovectomy,radiation beam therapy, radio isotope synovectomy, and jointreplacement. In some embodiments, the tumor is unresectable. In someembodiments, the subject has not received prior therapy with imatinib ornilotinib, while in other embodiments the subject has received priortreatment with imatinib or nilotinib. In some embodiments, the subjecthas not received prior treatment with a CSF1R inhibitor, while in otherembodiments the subject has received prior treatment with a CSF1Rinhibitor.

In any of the compositions or methods described herein, the antibodyheavy chain and/or the antibody light chain of the anti-CSF1R antibodymay have the structure described below.

In any of the compositions or methods described herein, the anti-CSF1Rantibody heavy chain may comprise a sequence that is at least 90%, atleast 95%, at least 97%, at least 99%, or 100% identical to a sequenceselected from SEQ ID NOs: 9, 11, 13, and 39 to 45. In any of the methodsdescribed herein, the anti-CSF1R antibody light chain may comprise asequence that is at least 90%, at least 95%, at least 97%, at least 99%,or 100% identical to a sequence selected from SEQ ID NOs: 10, 12, 14,and 46 to 52. In any of the compositions or methods described herein,the anti-CSF1R antibody heavy chain may comprise a sequence that is atleast 90%, at least 95%, at least 97%, at least 99%, or 100% identicalto a sequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45, and theanti-CSF1R antibody light chain may comprise a sequence that is at least90%, at least 95%, at least 97%, at least 99%, or 100% identical to asequence selected from SEQ ID NOs: 10, 12, 14, and 46 to 52.

In any of the compositions or methods described herein, the anti-CSF1Rantibody HC CDR1, HC CDR2, and HC CDR3 may comprise a set of sequencesselected from: (a) SEQ ID NOs: 15, 16, and 17; (b) SEQ ID NOs: 21, 22,and 23; and (c) SEQ ID NOs: 27, 28, and 29. In any of the compositionsor methods described herein, the anti-CSF1R antibody LC CDR1, LC CDR2,and LC CDR3 may comprise a set of sequences selected from: (a) SEQ IDNOs: 18, 19, and 20; (b) SEQ ID NOs: 24, 25, and 26; and (c) SEQ ID NOs:30, 31, and 32.

In any of the compositions or methods described herein, the anti-CSF1Rantibody heavy chain may comprise an HC CDR1, HC CDR2, and HC CDR3,wherein the HC CDR1, HC CDR2, and HC CDR3 comprise a set of sequencesselected from: (a) SEQ ID NOs: 15, 16, and 17; (b) SEQ ID NOs: 21, 22,and 23; and (c) SEQ ID NOs: 27, 28, and 29; and the light chain maycomprise an LC CDR1, LC CDR2, and LC CDR3, wherein the LC CDR1, LC CDR2,and LC CDR3 comprise a set of sequences selected from: (a) SEQ ID NOs:18, 19, and 20; (b) SEQ ID NOs: 24, 25, and 26; and (c) SEQ ID NOs: 30,31, and 32.

In any of the compositions or methods described herein, the anti-CSF1Rantibody may comprise: (a) a heavy chain comprising a sequence that isat least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 9 and a light chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 10; (b) a heavychain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 11 and a light chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 12; (c) a heavy chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 13 and a light chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 14; (d) a heavychain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 39 and a light chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 46; (e) a heavy chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 40 and a light chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 46; (f) a heavychain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 41 and a light chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 46; (g) a heavy chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 39 and a light chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 47; (h) a heavychain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 40 and a light chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 47; (i) a heavy chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 41 and a light chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 47; and (j) aheavy chain comprising a sequence that is at least 95%, at least 97%, atleast 99%, or 100% identical to SEQ ID NO: 42 and a light chaincomprising a sequence that is at least 95%, at least 97%, at least 99%,or 100% identical to SEQ ID NO: 48; (k) a heavy chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 42 and a light chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 49; (1) a heavy chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 42 and a lightchain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 50; (m) a heavy chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 43 and a light chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 48; (n) a heavy chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 43 and a lightchain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 49; (o) a heavy chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 43 and a light chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 50; (p) a heavy chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 44 and a lightchain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 51; (q) a heavy chain comprising asequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 44 and a light chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 52; (r) a heavy chain comprising a sequence that is at least 95%, atleast 97%, at least 99%, or 100% identical to SEQ ID NO: 45 and a lightchain comprising a sequence that is at least 95%, at least 97%, at least99%, or 100% identical to SEQ ID NO: 51; or (s) a heavy chain comprisinga sequence that is at least 95%, at least 97%, at least 99%, or 100%identical to SEQ ID NO: 45 and a light chain comprising a sequence thatis at least 95%, at least 97%, at least 99%, or 100% identical to SEQ IDNO: 52.

In any of the compositions or methods described herein, the anti-CSF1Rantibody may comprise: (a) a heavy chain comprising a heavy chain (HC)CDR1 having the sequence of SEQ ID NO: 15, an HC CDR2 having thesequence of SEQ ID NO: 16, and an HC CDR3 having the sequence of SEQ IDNO: 17, and a light chain comprising a light chain (LC) CDR1 having thesequence of SEQ ID NO: 18, a LC CDR2 having the sequence of SEQ ID NO:19, and a LC CDR3 having the sequence of SEQ ID NO: 20; (b) a heavychain comprising a heavy chain (HC) CDR1 having the sequence of SEQ IDNO: 21, an HC CDR2 having the sequence of SEQ ID NO: 22, and an HC CDR3having the sequence of SEQ ID NO: 23, and a light chain comprising alight chain (LC) CDR1 having the sequence of SEQ ID NO: 24, a LC CDR2having the sequence of SEQ ID NO: 25, and a LC CDR3 having the sequenceof SEQ ID NO: 26; or (c) a heavy chain comprising a heavy chain (HC)CDR1 having the sequence of SEQ ID NO: 27, an HC CDR2 having thesequence of SEQ ID NO: 28, and an HC CDR3 having the sequence of SEQ IDNO: 29, and a light chain comprising a light chain (LC) CDR1 having thesequence of SEQ ID NO: 30, a LC CDR2 having the sequence of SEQ ID NO:31, and a LC CDR3 having the sequence of SEQ ID NO: 32.

In any of the compositions or methods described herein, the anti-CSF1Rantibody may comprise: (a) a heavy chain comprising a sequence of SEQ IDNO: 53 and a light chain comprising a sequence of SEQ ID NO: 60; (b) aheavy chain comprising a sequence of SEQ ID NO: 53 and a light chaincomprising a sequence of SEQ ID NO: 61; or (c) a heavy chain comprisinga sequence of SEQ ID NO: 58 and a light chain comprising a sequence ofSEQ ID NO: 65. In some embodiments, an antibody comprises a heavy chainand a light chain, wherein the antibody comprises: (a) a heavy chainconsisting of the sequence of SEQ ID NO: 53 and a light chain consistingof the sequence of SEQ ID NO: 60; (b) a heavy chain consisting of thesequence of SEQ ID NO: 53 and a light chain consisting of the sequenceof SEQ ID NO: 61; or (c) a heavy chain consisting of the sequence of SEQID NO: 58 and a light chain consisting of the sequence of SEQ ID NO: 65.

In any of the compositions or methods described herein, the anti-CSF1Rantibody may be a humanized antibody. In any of the compositions ormethods described herein, the anti-CSF1R antibody may be any of huAb1,huAb2, huAb3, huAb4, huAb5 huAb6, huAb7, huAb8, huAb9, huAb10, huAb11,huAb12, huAb13, huAb14 huAb15, or huAb16. (See FIGS. 1-2.) In any of thecompositions or methods described herein, the anti-CSF1R antibody may beselected from a Fab, an Fv, an scFv, a Fab′, and a (Fab′)₂. In any ofthe compositions or methods described herein, the anti-CSF1R antibodymay be a chimeric antibody. In any of the compositions or methodsdescribed herein, the anti-CSF1R antibody may be selected from an IgA,an IgG, and an IgD. In any of the compositions or methods describedherein, the anti-CSF1R antibody may be an IgG. In any of the methodsdescribed herein, the antibody may be an IgG1 or IgG2.

In any of the compositions or methods described herein, the anti-CSF1Rantibody may bind to human CSF1R and/or binds to cynomolgus CSF1R. Inany of the compositions or methods described herein, the anti-CSF1Rantibody may block ligand binding to CSF1R. In any of the compositionsor methods described herein, the anti-CSF1R antibody may block bindingof CSF1 and/or IL-34 to CSF1R. In any of the compositions or methodsdescribed herein, the anti-CSF1R antibody may block binding of both CSF1and IL-34 to CSF1R. In any of the compositions or methods describedherein, the anti-CSF1R antibody may inhibit ligand-induced CSF1Rphosphorylation. In any of the compositions or methods described herein,the anti-CSF1R antibody may inhibit CSF1- and/or IL-34-induced CSF1Rphosphorylation. In any of the compositions or methods described herein,the anti-CSF1R antibody may bind to human CSF1R with an affinity (K_(D))of less than 1 nM. In any of the compositions or methods describedherein, the anti-CSF1R antibody may inhibit monocyte proliferationand/or survival responses in the presence of CSF1 or IL-34.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A-C show an alignment of the humanized heavy chain variableregions for each of humanized antibodies huAb1 to huAb16, as discussedin Example 1. Boxed residues are amino acids in the human acceptorsequence that were changed back to the corresponding mouse residue.

FIG. 2A-C show an alignment of the humanized light chain variableregions for each of humanized antibodies huAb1 to huAb16, as discussedin Example 1. Boxed amino acids are residues in the human acceptorsequence that were changed back to the corresponding mouse residue.

FIG. 3 shows a schematic diagram of the clinical trial summarized inExamples 4 and 5 using antibody huAb1, also known as FPA008.

DETAILED DESCRIPTION

The present invention provides methods of treating PVNS in a subjectcomprising administering an anti-CSF1R antibody to the subject.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All references cited herein, including patent applications andpublications, are incorporated herein by reference in their entiretiesfor any purpose.

Definitions

Unless otherwise defined, scientific and technical terms used inconnection with the present invention shall have the meanings that arecommonly understood by those of ordinary skill in the art. Further,unless otherwise required by context, singular terms shall includepluralities and plural terms shall include the singular.

Exemplary techniques used in connection with recombinant DNA,oligonucleotide synthesis, tissue culture and transformation (e.g.,electroporation, lipofection), enzymatic reactions, and purificationtechniques are known in the art. Many such techniques and procedures aredescribed, e.g., in Sambrook et al. Molecular Cloning: A LaboratoryManual (2nd ed., Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y. (1989)), among other places. In addition, exemplarytechniques for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients arealso known in the art.

In this application, the use of “or” means “and/or” unless statedotherwise. In the context of a multiple dependent claim, the use of “or”refers back to more than one preceding independent or dependent claim inthe alternative only. Also, terms such as “element” or “component”encompass both elements and components comprising one unit and elementsand components that comprise more than one subunit unless specificallystated otherwise.

As utilized in accordance with the present disclosure, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

The terms “nucleic acid molecule” and “polynucleotide” may be usedinterchangeably, and refer to a polymer of nucleotides. Such polymers ofnucleotides may contain natural and/or non-natural nucleotides, andinclude, but are not limited to, DNA, RNA, and PNA. “Nucleic acidsequence” refers to the linear sequence of nucleotides that comprise thenucleic acid molecule or polynucleotide.

The terms “polypeptide” and “protein” are used interchangeably to referto a polymer of amino acid residues, and are not limited to a minimumlength. Such polymers of amino acid residues may contain natural ornon-natural amino acid residues, and include, but are not limited to,peptides, oligopeptides, dimers, trimers, and multimers of amino acidresidues. Both full-length proteins and fragments thereof areencompassed by the definition. The terms also include post-expressionmodifications of the polypeptide, for example, glycosylation,sialylation, acetylation, phosphorylation, and the like. Furthermore,for purposes of the present invention, a “polypeptide” refers to aprotein which includes modifications, such as deletions, additions, andsubstitutions (generally conservative in nature), to the nativesequence, as long as the protein maintains the desired activity. Thesemodifications may be deliberate, as through site-directed mutagenesis,or may be accidental, such as through mutations of hosts which producethe proteins or errors due to PCR amplification.

The term “CSF1R” refers herein to the full-length CSF1R, which includesthe N-terminal ECD, the transmembrane domain, and the intracellulartyrosine kinase domain, with or without an N-terminal leader sequence.In some embodiments, the CSF1R is a human CSF1R having the amino acidsequence of SEQ ID NO: 1 or SEQ ID NO: 2.

With reference to anti-CSF1R antibodies the term “blocks binding of” aligand, such as CSF1 and/or IL-34, and grammatical variants thereof, areused to refer to the ability to inhibit the interaction between CSF1Rand a CSF1R ligand, such as CSF1 and/or IL-34. Such inhibition may occurthrough any mechanism, including direct interference with ligandbinding, e.g., because of overlapping binding sites on CSF1R, and/orconformational changes in CSF1R induced by the antibody that alterligand affinity, etc. Antibodies and antibody fragments referred to as“functional” are characterized by having such properties.

The term “antibody” as used herein refers to a molecule comprising atleast complementarity-determining region (CDR) 1, CDR2, and CDR3 of aheavy chain and at least CDR1, CDR2, and CDR3 of a light chain, whereinthe molecule is capable of binding to antigen. The term antibodyincludes, but is not limited to, fragments that are capable of bindingantigen, such as Fv, single-chain Fv (scFv), Fab, Fab′, and (Fab′)₂. Theterm antibody also includes, but is not limited to, chimeric antibodies,humanized antibodies, and antibodies of various species such as mouse,human, cynomolgus monkey, etc.

In some embodiments, an antibody comprises a heavy chain variable regionand a light chain variable region. In some embodiments, an antibodycomprises at least one heavy chain comprising a heavy chain variableregion and at least a portion of a heavy chain constant region, and atleast one light chain comprising a light chain variable region and atleast a portion of a light chain constant region. In some embodiments,an antibody comprises two heavy chains, wherein each heavy chaincomprises a heavy chain variable region and at least a portion of aheavy chain constant region, and two light chains, wherein each lightchain comprises a light chain variable region and at least a portion ofa light chain constant region. As used herein, a single-chain Fv (scFv),or any other antibody that comprises, for example, a single polypeptidechain comprising all six CDRs (three heavy chain CDRs and three lightchain CDRs) is considered to have a heavy chain and a light chain. Insome such embodiments, the heavy chain is the region of the antibodythat comprises the three heavy chain CDRs and the light chain in theregion of the antibody that comprises the three light chain CDRs.

The term “heavy chain variable region” as used herein refers to a regioncomprising heavy chain CDR1, framework (FR) 2, CDR2, FR3, and CDR3. Insome embodiments, a heavy chain variable region also comprises at leasta portion of an FR1 and/or at least a portion of an FR4. In someembodiments, a heavy chain CDR1 corresponds to Kabat residues 26 to 35;a heavy chain CDR2 corresponds to Kabat residues 50 to 65; and a heavychain CDR3 corresponds to Kabat residues 95 to 102. See, e.g., KabatSequences of Proteins of Immunological Interest (1987 and 1991, NIH,Bethesda, Md.); and FIG. 1. In some embodiments, a heavy chain CDR1corresponds to Kabat residues 31 to 35; a heavy chain CDR2 correspondsto Kabat residues 50 to 65; and a heavy chain CDR3 corresponds to Kabatresidues 95 to 102. See id.

The term “heavy chain constant region” as used herein refers to a regioncomprising at least three heavy chain constant domains, C_(H)1, C_(H)2,and C_(H)3. Nonlimiting exemplary heavy chain constant regions includeγ, δ, and α. Nonlimiting exemplary heavy chain constant regions alsoinclude ε and μ. Each heavy constant region corresponds to an antibodyisotype. For example, an antibody comprising a γ constant region is anIgG antibody, an antibody comprising a δ constant region is an IgDantibody, and an antibody comprising an α constant region is an IgAantibody. Further, an antibody comprising a μ constant region is an IgMantibody, and an antibody comprising an ε constant region is an IgEantibody. Certain isotypes can be further subdivided into subclasses.For example, IgG antibodies include, but are not limited to, IgG1(comprising a γ₁ constant region), IgG2 (comprising a γ₂ constantregion), IgG3 (comprising a γ₃ constant region), and IgG4 (comprising aγ₄ constant region) antibodies; IgA antibodies include, but are notlimited to, IgA1 (comprising an α₁ constant region) and IgA2 (comprisingan α₂ constant region) antibodies; and IgM antibodies include, but arenot limited to, IgM1 and IgM2.

In some embodiments, a heavy chain constant region comprises one or moremutations (or substitutions), additions, or deletions that confer adesired characteristic on the antibody. A nonlimiting exemplary mutationis the S241P mutation in the IgG4 hinge region (between constant domainsC_(H)1 and C_(H)2), which alters the IgG4 motif CPSCP to CPPCP, which issimilar to the corresponding motif in IgG1. That mutation, in someembodiments, results in a more stable IgG4 antibody. See, e.g., Angal etal., Mol. Immunol. 30: 105-108 (1993); Bloom et al., Prot. Sci. 6:407-415 (1997); Schuurman et al., Mol. Immunol. 38: 1-8 (2001).

The term “heavy chain” as used herein refers to a polypeptide comprisingat least a heavy chain variable region, with or without a leadersequence. In some embodiments, a heavy chain comprises at least aportion of a heavy chain constant region. The term “full-length heavychain” as used herein refers to a polypeptide comprising a heavy chainvariable region and a heavy chain constant region, with or without aleader sequence.

The term “light chain variable region” as used herein refers to a regioncomprising light chain CDR1, framework (FR) 2, CDR2, FR3, and CDR3. Insome embodiments, a light chain variable region also comprises an FR1and/or an FR4. In some embodiments, a light chain CDR1 corresponds toKabat residues 24 to 34; a light chain CDR2 corresponds to Kabatresidues 50 to 56; and a light chain CDR3 corresponds to Kabat residues89 to 97. See, e.g., Kabat Sequences of Proteins of ImmunologicalInterest (1987 and 1991, Bethesda, Md.); and FIG. 1.

The term “light chain constant region” as used herein refers to a regioncomprising a light chain constant domain, C_(L). Nonlimiting exemplarylight chain constant regions include λ and κ.

The term “light chain” as used herein refers to a polypeptide comprisingat least a light chain variable region, with or without a leadersequence. In some embodiments, a light chain comprises at least aportion of a light chain constant region. The term “full-length lightchain” as used herein refers to a polypeptide comprising a light chainvariable region and a light chain constant region, with or without aleader sequence.

A “chimeric antibody” as used herein refers to an antibody comprising atleast one variable region from a first species (such as mouse, rat,cynomolgus monkey, etc.) and at least one constant region from a secondspecies (such as human, cynomolgus monkey, etc.). In some embodiments, achimeric antibody comprises at least one mouse variable region and atleast one human constant region. In some embodiments, a chimericantibody comprises at least one cynomolgus variable region and at leastone human constant region. In some embodiments, a chimeric antibodycomprises at least one rat variable region and at least one mouseconstant region. In some embodiments, all of the variable regions of achimeric antibody are from a first species and all of the constantregions of the chimeric antibody are from a second species.

A “humanized antibody” as used herein refers to an antibody in which atleast one amino acid in a framework region of a non-human variableregion has been replaced with the corresponding amino acid from a humanvariable region. In some embodiments, a humanized antibody comprises atleast one human constant region or fragment thereof. In someembodiments, a humanized antibody is a Fab, an scFv, a (Fab′)₂, etc.

A “CDR-grafted antibody” as used herein refers to a humanized antibodyin which the complementarity determining regions (CDRs) of a first(non-human) species have been grafted onto the framework regions (FRs)of a second (human) species.

A “human antibody” as used herein refers to antibodies produced inhumans, antibodies produced in non-human animals that comprise humanimmunoglobulin genes, such as XenoMouse®, and antibodies selected usingin vitro methods, such as phage display, wherein the antibody repertoireis based on a human immunoglobulin sequences.

The term “leader sequence” refers to a sequence of amino acid residueslocated at the N terminus of a polypeptide that facilitates secretion ofa polypeptide from a mammalian cell. A leader sequence may be cleavedupon export of the polypeptide from the mammalian cell, forming a matureprotein. Leader sequences may be natural or synthetic, and they may beheterologous or homologous to the protein to which they are attached.Exemplary leader sequences include, but are not limited to, antibodyleader sequences, such as, for example, the amino acid sequences of SEQID NOs: 3 and 4, which correspond to human light and heavy chain leadersequences, respectively. Nonlimiting exemplary leader sequences alsoinclude leader sequences from heterologous proteins. In someembodiments, an antibody lacks a leader sequence. In some embodiments,an antibody comprises at least one leader sequence, which may beselected from native antibody leader sequences and heterologous leadersequences.

The term “vector” is used to describe a polynucleotide that may beengineered to contain a cloned polynucleotide or polynucleotides thatmay be propagated in a host cell. A vector may include one or more ofthe following elements: an origin of replication, one or more regulatorysequences (such as, for example, promoters and/or enhancers) thatregulate the expression of the polypeptide of interest, and/or one ormore selectable marker genes (such as, for example, antibioticresistance genes and genes that may be used in colorimetric assays,e.g., β-galactosidase). The term “expression vector” refers to a vectorthat is used to express a polypeptide of interest in a host cell.

A “host cell” refers to a cell that may be or has been a recipient of avector or isolated polynucleotide. Host cells may be prokaryotic cellsor eukaryotic cells. Exemplary eukaryotic cells include mammalian cells,such as primate or non-primate animal cells; fungal cells, such asyeast; plant cells; and insect cells. Nonlimiting exemplary mammaliancells include, but are not limited to, NSO cells, PER.C6® cells(Crucell), and 293 and CHO cells, and their derivatives, such as 293-6Eand DG44 cells, respectively.

The term “isolated” as used herein refers to a molecule that has beenseparated from at least some of the components with which it istypically found in nature. For example, a polypeptide is referred to as“isolated” when it is separated from at least some of the components ofthe cell in which it was produced. Where a polypeptide is secreted by acell after expression, physically separating the supernatant containingthe polypeptide from the cell that produced it is considered to be“isolating” the polypeptide. Similarly, a polynucleotide is referred toas “isolated” when it is not part of the larger polynucleotide (such as,for example, genomic DNA or mitochondrial DNA, in the case of a DNApolynucleotide) in which it is typically found in nature, or isseparated from at least some of the components of the cell in which itwas produced, e.g., in the case of an RNA polynucleotide. Thus, a DNApolynucleotide that is contained in a vector inside a host cell may bereferred to as “isolated” so long as that polynucleotide is not found inthat vector in nature.

The term “elevated level” means a higher level of a protein in aparticular tissue of a subject relative to the same tissue in a control,such as an individual or individuals who are not suffering from PVNS orother condition described herein. The elevated level may be the resultof any mechanism, such as increased expression, increased stability,decreased degradation, increased secretion, decreased clearance, etc.,of the protein.

The term “reduce” or “reduces” means to lower the level of a protein ina particular tissue of a subject by at least 10%. In some embodiments,an agent, such as an antibody that binds CSF1R, reduces the level of aprotein in a particular tissue of a subject by at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, or at least 90%. In someembodiments, the level of a protein is reduced relative to the level ofthe protein prior to contacting with an agent, such as an antibody thatbinds CSF1R.

The term “resistant,” when used in the context of resistance to atherapeutic agent, means a decreased response or lack of response to astandard dose of the therapeutic agent, relative to the subject'sresponse to the standard dose of the therapeutic agent in the past, orrelative to the expected response of a similar subject with a similardisorder to the standard dose of the therapeutic agent. Thus, in someembodiments, a subject may be resistant to therapeutic agent althoughthe subject has not previously been given the therapeutic agent, or thesubject may develop resistance to the therapeutic agent after havingresponded to the agent on one or more previous occasions.

The terms “subject” and “patient” are used interchangeably herein torefer to a human. In some embodiments, methods of treating othermammals, including, but not limited to, rodents, simians, felines,canines, equines, bovines, porcines, ovines, caprines, mammalianlaboratory animals, mammalian farm animals, mammalian sport animals, andmammalian pets, are also provided.

The term “sample,” as used herein, refers to a composition that isobtained or derived from a subject that contains a cellular and/or othermolecular entity that is to be characterized, quantitated, and/oridentified, for example based on physical, biochemical, chemical and/orphysiological characteristics. An exemplary sample is a tissue sample.

The term “tissue sample” refers to a collection of similar cellsobtained from a tissue of a subject. The source of the tissue sample maybe solid tissue as from a fresh, frozen and/or preserved organ or tissuesample or biopsy or aspirate; blood or any blood constituents; bodilyfluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid,synovial fluid, or interstitial fluid; cells from any time in gestationor development of the subject. In some embodiments, a tissue sample is asynovial biopsy tissue sample and/or a synovial fluid sample. In someembodiments, a tissue sample is a synovial fluid sample. The tissuesample may also be primary or cultured cells or cell lines. Optionally,the tissue sample is obtained from a disease tissue/organ. The tissuesample may contain compounds that are not naturally intermixed with thetissue in nature such as preservatives, anticoagulants, buffers,fixatives, nutrients, antibiotics, or the like. A “control sample” or“control tissue”, as used herein, refers to a sample, cell, or tissueobtained from a source known, or believed, not to be afflicted with thedisease for which the subject is being treated.

For the purposes herein a “section” of a tissue sample means a part orpiece of a tissue sample, such as a thin slice of tissue or cells cutfrom a solid tissue sample.

The term “pigmented villonodular synovitis” or “PVNS” as used hereinrefers to a condition in which the synovium thickens and overgrows inone or more joints. Localized PVNS typically involves the tendons thatsupport the joint and/or occurs in one area of the joint, while diffusePVNS is more widespread and may involve the entire joint. Diffuse PVNStypically affects large joints, such as the hip and/or knee joints,while localized (or nodular) PVNS typically occurs in smaller jointssuch as the hands and feet. The benign growth (sometimes referred to asa benign tumor) may progress, leading to damage to adjacent bone and/orarthritis. The methods of treating PVNS disclosed in the presentapplication can also be used in treating other proliferative disordersthat involve synovial joints and tendon sheaths, such as giant celltumor of the tendon sheath (GCTTS) and tenosynovial giant cell tumor(TGCT) such as diffuse type tenosynovial giant cell tumor (dtTGCT).

An agent “antagonizes” factor activity when the agent neutralizes,blocks, inhibits, abrogates, reduces, and/or interferes with theactivity of the factor, including its binding to one or more receptorswhen the factor is a ligand.

“Treatment,” as used herein, refers to both therapeutic treatment andprophylactic or preventative measures, wherein the object is to preventor slow down (lessen) the targeted pathologic condition or disorder. Incertain embodiments, the term “treatment” covers any administration orapplication of a therapeutic for disease in a mammal, including a human,and includes inhibiting or slowing the disease or progression of thedisease; partially or fully relieving the disease, for example, bycausing regression, or restoring or repairing a lost, missing, ordefective function; stimulating an inefficient process; or causing thedisease plateau to have reduced severity. The term “treatment” alsoincludes reducing the severity of any phenotypic characteristic and/orreducing the incidence, degree, or likelihood of that characteristic.Those in need of treatment include those already with the disorder aswell as those prone to have the disorder or those in whom the disorderis to be prevented.

The term “effective amount” or “therapeutically effective amount” refersto an amount of a drug effective to treat a disease or disorder in asubject. In certain embodiments, an effective amount refers to an amounteffective, at dosages and for periods of time necessary, to achieve thedesired therapeutic or prophylactic result. A therapeutically effectiveamount of an anti-CSF1R antibody of the invention may vary according tofactors such as the disease state, age, sex, and weight of theindividual, and the ability of the antibody or antibodies to elicit adesired response in the individual. A therapeutically effective amountencompasses an amount in which any toxic or detrimental effects of theantibody or antibodies are outweighed by the therapeutically beneficialeffects. In some embodiments, the expression “effective amount” refersto an amount of the antibody that is effective for treating PVNS.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, but not necessarily, since aprophylactic dose is used in subjects prior to or at an earlier stage ofdisease, the prophylactically effective amount would be less than thetherapeutically effective amount.

Administration “in combination with” one or more further therapeuticagents includes simultaneous (concurrent) and consecutive (sequential)administration in any order.

A “pharmaceutically acceptable carrier” refers to a non-toxic solid,semisolid, or liquid filler, diluent, encapsulating material,formulation auxiliary, or carrier conventional in the art for use with atherapeutic agent that together comprise a “pharmaceutical composition”for administration to a subject. A pharmaceutically acceptable carrieris non-toxic to recipients at the dosages and concentrations employedand is compatible with other ingredients of the formulation. Thepharmaceutically acceptable carrier is appropriate for the formulationemployed. For example, if the therapeutic agent is to be administeredorally, the carrier may be a gel capsule. If the therapeutic agent is tobe administered subcutaneously, the carrier ideally is not irritable tothe skin and does not cause injection site reaction.

Anti-CSF1R Antibodies

Anti-CSF1R antibodies include, but are not limited to, humanizedantibodies, chimeric antibodies, mouse antibodies, human antibodies, andantibodies comprising the heavy chain and/or light chain CDRs discussedherein.

Exemplary Humanized Antibodies

In some embodiments, humanized antibodies that bind CSF1R are provided.Humanized antibodies are useful as therapeutic molecules becausehumanized antibodies reduce or eliminate the human immune response tonon-human antibodies (such as the human anti-mouse antibody (HAMA)response), which can result in an immune response to an antibodytherapeutic, and decreased effectiveness of the therapeutic.

Nonlimiting exemplary humanized antibodies include huAb1 through huAb16,described herein. Nonlimiting exemplary humanized antibodies alsoinclude antibodies comprising a heavy chain variable region of anantibody selected from huAb1 to huAb16 and/or a light chain variableregion of an antibody selected from huAb1 to huAb16. Nonlimitingexemplary humanized antibodies include antibodies comprising a heavychain variable region selected from SEQ ID NOs: 39 to 45 and/or a lightchain variable region selected from SEQ ID NOs: 46 to 52. Exemplaryhumanized antibodies also include, but are not limited to, humanizedantibodies comprising heavy chain CDR1, CDR2, and CDR3, and/or lightchain CDR1, CDR2, and CDR3 of an antibody selected from 0301, 0302, and0311.

In some embodiments, a humanized anti-CSF1R antibody comprises heavychain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, and CDR3 ofan antibody selected from 0301, 0302, and 0311. Nonlimiting exemplaryhumanized anti-CSF1R antibodies include antibodies comprising sets ofheavy chain CDR1, CDR2, and CDR3 selected from: SEQ ID NOs: 15, 16, and17; SEQ ID NOs: 21, 22, and 23; and SEQ ID NOs: 27, 28, and 29.Nonlimiting exemplary humanized anti-CSF1R antibodies also includeantibodies comprising sets of light chain CDR1, CDR2, and CDR3 selectedfrom: SEQ ID NOs: 18, 19, and 20; SEQ ID NOs: 24, 25, and 26; and SEQ IDNOs: 30, 31, and 32.

Nonlimiting exemplary humanized anti-CSF1R antibodies include antibodiescomprising the sets of heavy chain CDR1, CDR2, and CDR3, and light chainCDR1, CDR2, and CDR3 in Table 1 (SEQ ID NOs shown; see Table 8 forsequences). Each row of Table 1 shows the heavy chain CDR1, CDR2, andCDR3, and light chain CDR1, CDR2, and CDR3 of an exemplary antibody.

TABLE 1 Heavy chain and light chain CDRs Heavy chain Light chain CDR1CDR2 CDR3 CDR1 CDR2 CDR3 Ab SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID0301 15 16 17 18 19 20 0302 21 22 23 24 25 26 0311 27 28 29 30 31 32

Further Exemplary Humanized Antibodies

In some embodiments, a humanized anti-CSF1R antibody comprises a heavychain comprising a variable region sequence that is at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99% identical to asequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45, and whereinthe antibody binds CSF1R. In some embodiments, a humanized anti-CSF1Rantibody comprises a light chain comprising a variable region sequencethat is at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least99% identical to a sequence selected from SEQ ID NOs: 10, 12, 14, and 46to 52, wherein the antibody binds CSF1R. In some embodiments, ahumanized anti-CSF1R antibody comprises a heavy chain comprising avariable region sequence that is at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% identical to a sequence selected fromSEQ ID NOs: 9, 11, 13, and 39 to 45; and a light chain comprising avariable region sequence that is at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% identical to a sequence selected fromSEQ ID NOs: 10, 12, 14, and 46 to 52; wherein the antibody binds CSF1R.

As used herein, whether a particular polypeptide is, for example, atleast 95% identical to an amino acid sequence can be determined using,e.g., a computer program. When determining whether a particular sequenceis, for example, 95% identical to a reference sequence, the percentageof identity is calculated over the full length of the reference aminoacid sequence.

In some embodiments, a humanized anti-CSF1R antibody comprises at leastone of the CDRs discussed herein. That is, in some embodiments, ahumanized anti-CSF1R antibody comprises at least one CDR selected from aheavy chain CDR1 discussed herein, a heavy chain CDR2 discussed herein,a heavy chain CDR3 discussed herein, a light chain CDR1 discussedherein, a light chain CDR2 discussed herein, and a light chain CDR3discussed herein. Further, in some embodiments, a humanized anti-CSF1Rantibody comprises at least one mutated CDR based on a CDR discussedherein, wherein the mutated CDR comprises 1, 2, 3, or 4 amino acidsubstitutions relative to the CDR discussed herein. In some embodiments,one or more of the amino acid substitutions are conservative amino acidsubstitutions. One skilled in the art can select one or more suitableconservative amino acid substitutions for a particular CDR sequence,wherein the suitable conservative amino acid substitutions are notpredicted to significantly alter the binding properties of the antibodycomprising the mutated CDR.

Exemplary humanized anti-CSF1R antibodies also include antibodies thatcompete for binding to CSF1R with an antibody described herein. Thus, insome embodiments, a humanized anti-CSF1R antibody is provided thatcompetes for binding to CSF1R with an antibody selected from Fabs 0301,0302, and 0311; and bivalent (i.e., having two heavy chains and twolight chains) antibody versions of those Fabs.

Exemplary Humanized Antibody Constant Regions

In some embodiments, a humanized antibody described herein comprises oneor more human constant regions. In some embodiments, the human heavychain constant region is of an isotype selected from IgA, IgG, and IgD.In some embodiments, the human light chain constant region is of anisotype selected from κ and λ. In some embodiments, a humanized antibodydescribed herein comprises a human IgG constant region. In someembodiments, a humanized antibody described herein comprises a humanIgG4 heavy chain constant region. In some such embodiments, a humanizedantibody described herein comprises an S241P mutation in the human IgG4constant region. In some embodiments, a humanized antibody describedherein comprises a human IgG4 constant region and a human κ light chain.

The choice of heavy chain constant region can determine whether or notan antibody will have effector function in vivo. Such effector function,in some embodiments, includes antibody-dependent cell-mediatedcytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC), andcan result in killing of the cell to which the antibody is bound. Insome methods of treatment, including methods of treating some tumors,cell killing may be desirable, for example, when the antibody binds to acell that supports the maintenance or growth of the tumor. Exemplarycells that may support the maintenance or growth of a tumor include, butare not limited to, tumor cells themselves, cells that aid in therecruitment of vasculature to the tumor, and cells that provide ligands,growth factors, or counter-receptors that support or promote tumorgrowth or tumor survival. In some embodiments, when effector function isdesirable, an anti-CSF1R antibody comprising a human IgG1 heavy chain ora human IgG3 heavy chain is selected.

In some methods of treatment, effector function may not be desirable.For example, in some embodiments, it may be desirable that antibodiesused in the treatment of PVNS do not have effector function.Accordingly, in some embodiments, an anti-CSF1R antibody that lackssignificant effector function is used in treatment of PVNS. In someembodiments, an anti-CSF1R antibody for treatment of PVNS comprises ahuman IgG4 or IgG2 heavy chain constant region. In some embodiments, anIgG4 constant region comprises an S241P mutation.

An antibody may be humanized by any method. Nonlimiting exemplarymethods of humanization include methods described, e.g., in U.S. Pat.Nos. 5,530,101; 5,585,089; 5,693,761; 5,693,762; 6,180,370; Jones etal., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-27(1988); Verhoeyen et al., Science 239: 1534-36 (1988); and U.S.Publication No. US 2009/0136500.

As noted above, a humanized antibody is an antibody in which at leastone amino acid in a framework region of a non-human variable region hasbeen replaced with the amino acid from the corresponding location in ahuman framework region. In some embodiments, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, at least nine, at least 10, at least 11, at least 12, atleast 15, or at least 20 amino acids in the framework regions of anon-human variable region are replaced with an amino acid from one ormore corresponding locations in one or more human framework regions.

In some embodiments, some of the corresponding human amino acids usedfor substitution are from the framework regions of different humanimmunoglobulin genes. That is, in some such embodiments, one or more ofthe non-human amino acids may be replaced with corresponding amino acidsfrom a human framework region of a first human antibody or encoded by afirst human immunoglobulin gene, one or more of the non-human aminoacids may be replaced with corresponding amino acids from a humanframework region of a second human antibody or encoded by a second humanimmunoglobulin gene, one or more of the non-human amino acids may bereplaced with corresponding amino acids from a human framework region ofa third human antibody or encoded by a third human immunoglobulin gene,etc. Further, in some embodiments, all of the corresponding human aminoacids being used for substitution in a single framework region, forexample, FR2, need not be from the same human framework. In someembodiments, however, all of the corresponding human amino acids beingused for substitution are from the same human antibody or encoded by thesame human immunoglobulin gene.

In some embodiments, an antibody is humanized by replacing one or moreentire framework regions with corresponding human framework regions. Insome embodiments, a human framework region is selected that has thehighest level of homology to the non-human framework region beingreplaced. In some embodiments, such a humanized antibody is aCDR-grafted antibody.

In some embodiments, following CDR-grafting, one or more framework aminoacids are changed back to the corresponding amino acid in a mouseframework region. Such “back mutations” are made, in some embodiments,to retain one or more mouse framework amino acids that appear tocontribute to the structure of one or more of the CDRs and/or that maybe involved in antigen contacts and/or appear to be involved in theoverall structural integrity of the antibody. In some embodiments, tenor fewer, nine or fewer, eight or fewer, seven or fewer, six or fewer,five or fewer, four or fewer, three or fewer, two or fewer, one, or zeroback mutations are made to the framework regions of an antibodyfollowing CDR grafting.

In some embodiments, a humanized antibody also comprises a human heavychain constant region and/or a human light chain constant region.

Exemplary Chimeric Antibodies

In some embodiments, an anti-CSF1R antibody is a chimeric antibody. Insome embodiments, an anti-CSF1R antibody comprises at least onenon-human variable region and at least one human constant region. Insome such embodiments, all of the variable regions of an anti-CSF1Rantibody are non-human variable regions, and all of the constant regionsof an anti-CSF1R antibody are human constant regions. In someembodiments, one or more variable regions of a chimeric antibody aremouse variable regions. The human constant region of a chimeric antibodyneed not be of the same isotype as the non-human constant region, ifany, it replaces. Chimeric antibodies are discussed, e.g., in U.S. Pat.No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA 81:6851-55 (1984).

Nonlimiting exemplary chimeric antibodies include chimeric antibodiescomprising the heavy and/or light chain variable regions of an antibodyselected from 0301, 0302, and 0311. Additional nonlimiting exemplarychimeric antibodies include chimeric antibodies comprising heavy chainCDR1, CDR2, and CDR3, and/or light chain CDR1, CDR2, and CDR3 of anantibody selected from 0301, 0302, and 0311.

Nonlimiting exemplary chimeric anti-CSF1R antibodies include antibodiescomprising the following pairs of heavy and light chain variableregions: SEQ ID NOs: 9 and 10; SEQ ID NOs: 11 and 12; and SEQ ID NOs: 13and 14.

Nonlimiting exemplary anti-CSF1R antibodies include antibodiescomprising a set of heavy chain CDR1, CDR2, and CDR3, and light chainCDR1, CDR2, and CDR3 shown above in Table 1.

Further Exemplary Chimeric Antibodies

In some embodiments, a chimeric anti-CSF1R antibody comprises a heavychain comprising a variable region sequence that is at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99% identical to asequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45, wherein theantibody binds CSF1R. In some embodiments, a chimeric anti-CSF1Rantibody comprises a light chain comprising a variable region sequencethat is at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least99% identical to a sequence selected from SEQ ID NOs: 10, 12, 14, and 46to 52, wherein the antibody binds CSF1R. In some embodiments, a chimericanti-CSF1R antibody comprises a heavy chain comprising a variable regionsequence that is at least 90%, at least 91%, at least 92%, at least 93%,at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, orat least 99% identical to a sequence selected from SEQ ID NOs: 9, 11,13, and 39 to 45; and a light chain comprising a variable regionsequence that is at least 90%, at least 91%, at least 92%, at least 93%,at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, orat least 99% identical to a sequence selected from SEQ ID NOs: 10, 12,14, and 46 to 52; wherein the antibody binds CSF1R.

In some embodiments, a chimeric anti-CSF1R antibody comprises at leastone of the CDRs discussed herein. That is, in some embodiments, achimeric anti-CSF1R antibody comprises at least one CDR selected from aheavy chain CDR1 discussed herein, a heavy chain CDR2 discussed herein,a heavy chain CDR3 discussed herein, a light chain CDR1 discussedherein, a light chain CDR2 discussed herein, and a light chain CDR3discussed herein. Further, in some embodiments, a chimeric anti-CSF1Rantibody comprises at least one mutated CDR based on a CDR discussedherein, wherein the mutated CDR comprises 1, 2, 3, or 4 amino acidsubstitutions relative to the CDR discussed herein. In some embodiments,one or more of the amino acid substitutions are conservative amino acidsubstitutions. One skilled in the art can select one or more suitableconservative amino acid substitutions for a particular CDR sequence,wherein the suitable conservative amino acid substitutions are notpredicted to significantly alter the binding properties of the antibodycomprising the mutated CDR.

Exemplary chimeric anti-CSF1R antibodies also include chimericantibodies that compete for binding to CSF1R with an antibody describedherein. Thus, in some embodiments, a chimeric anti-CSF1R antibody isprovided that competes for binding to CSF1R with an antibody selectedfrom Fabs 0301, 0302, and 0311; and bivalent (i.e., having two heavychains and two light chains) antibody versions of those Fabs.

Exemplary Chimeric Antibody Constant Regions

In some embodiments, a chimeric antibody described herein comprises oneor more human constant regions. In some embodiments, the human heavychain constant region is of an isotype selected from IgA, IgG, and IgD.In some embodiments, the human light chain constant region is of anisotype selected from κ and λ. In some embodiments, a chimeric antibodydescribed herein comprises a human IgG constant region. In someembodiments, a chimeric antibody described herein comprises a human IgG4heavy chain constant region. In some such embodiments, a chimericantibody described herein comprises an S241P mutation in the human IgG4constant region. In some embodiments, a chimeric antibody describedherein comprises a human IgG4 constant region and a human κ light chain.

As noted above, whether or not effector function is desirable may dependon the particular method of treatment intended for an antibody. Thus, insome embodiments, when effector function is desirable, a chimericanti-CSF1R antibody comprising a human IgG1 heavy chain constant regionor a human IgG3 heavy chain constant region is selected. In someembodiments, when effector function is not desirable, a chimericanti-CSF1R antibody comprising a human IgG4 or IgG2 heavy chain constantregion is selected.

Exemplary Human Antibodies

Human antibodies can be made by any suitable method. Nonlimitingexemplary methods include making human antibodies in transgenic micethat comprise human immunoglobulin loci. See, e.g., Jakobovits et al.,Proc. Natl. Acad. Sci. USA 90: 2551-55 (1993); Jakobovits et al., Nature362: 255-8 (1993); Lonberg et al., Nature 368: 856-9 (1994); and U.S.Pat. Nos. 5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,545,807;6,300,129; 6,255,458; 5,877,397; 5,874,299; and 5,545,806.

Nonlimiting exemplary methods also include making human antibodies usingphage display libraries. See, e.g., Hoogenboom et al., J. Mol. Biol.227: 381-8 (1992); Marks et al., J. Mol. Biol. 222: 581-97 (1991); andPCT Publication No. WO 99/10494.

In some embodiments, a human anti-CSF1R antibody binds to a polypeptidehaving the sequence of SEQ ID NO: 1. Exemplary human anti-CSF1Rantibodies also include antibodies that compete for binding to CSF1Rwith an antibody described herein. Thus, in some embodiments, a humananti-CSF1R antibody is provided that competes for binding to CSF1R withan antibody selected from Fabs 0301, 0302, and 0311, and bivalent (i.e.,having two heavy chains and two light chains) antibody versions of thoseFabs.

In some embodiments, a human anti-CSF1R antibody comprises one or morehuman constant regions. In some embodiments, the human heavy chainconstant region is of an isotype selected from IgA, IgG, and IgD. Insome embodiments, the human light chain constant region is of an isotypeselected from κ and λ. In some embodiments, a human antibody describedherein comprises a human IgG constant region. In some embodiments, ahuman antibody described herein comprises a human IgG4 heavy chainconstant region. In some such embodiments, a human antibody describedherein comprises an S241P mutation in the human IgG4 constant region. Insome embodiments, a human antibody described herein comprises a humanIgG4 constant region and a human κ light chain.

In some embodiments, when effector function is desirable, a humananti-CSF1R antibody comprising a human IgG1 heavy chain constant regionor a human IgG3 heavy chain constant region is selected. In someembodiments, when effector function is not desirable, a human anti-CSF1Rantibody comprising a human IgG4 or IgG2 heavy chain constant region isselected.

Additional Exemplary Anti-CSF1R Antibodies

Exemplary anti-CSF1R antibodies also include, but are not limited to,mouse, humanized, human, chimeric, and engineered antibodies thatcomprise, for example, one or more of the CDR sequences describedherein. In some embodiments, an anti-CSF1R antibody comprises a heavychain variable region described herein. In some embodiments, ananti-CSF1R antibody comprises a light chain variable region describedherein. In some embodiments, an anti-CSF1R antibody comprises a heavychain variable region described herein and a light chain variable regiondescribed herein. In some embodiments, an anti-CSF1R antibody comprisesheavy chain CDR1, CDR2, and CDR3 described herein. In some embodiments,an anti-CSF1R antibody comprises light chain CDR1, CDR2, and CDR3described herein. In some embodiments, an anti-CSF1R antibody comprisesheavy chain CDR1, CDR2, and CDR3 described herein and light chain CDR1,CDR2, and CDR3 described herein.

In some embodiments, an anti-CSF1R antibody comprises a heavy chainvariable region of an antibody selected from Fabs 0301, 0302, and 0311.Nonlimiting exemplary anti-CSF1R antibodies also include antibodiescomprising a heavy chain variable region of an antibody selected fromhumanized antibodies huAb1 to huAb16. Nonlimiting exemplary anti-CSF1Rantibodies include antibodies comprising a heavy chain variable regioncomprising a sequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45.

In some embodiments, an anti-CSF1R antibody comprises a light chainvariable region of an antibody selected from Fabs 0301, 0302, and 0311.Nonlimiting exemplary anti-CSF1R antibodies also include antibodiescomprising a light chain variable region of an antibody selected fromhumanized antibodies huAb1 to huAb16. Nonlimiting exemplary anti-CSF1Rantibodies include antibodies comprising a light chain variable regioncomprising a sequence selected from SEQ ID NOs: 10, 12, 14, and 46 to52.

In some embodiments, an anti-CSF1R antibody comprises a heavy chainvariable region and a light chain variable region of an antibodyselected from Fabs 0301, 0302, and 0311. Nonlimiting exemplaryanti-CSF1R antibodies also include antibodies comprising a heavy chainvariable region and a light chain variable region of an antibodyselected from humanized antibodies huAb1 to huAb16. Nonlimitingexemplary anti-CSF1R antibodies include antibodies comprising thefollowing pairs of heavy and light chain variable regions: SEQ ID NOs: 9and 10; SEQ ID NOs: 11 and 12; and SEQ ID NOs: 13 and 14; SEQ ID NOs: 39and 40; SEQ ID NOs: 41 and 42; SEQ ID NOs: 43 and 44; SEQ ID NOs: 45 and46; SEQ ID NOs: 47 and 48; SEQ ID NOs: 49 and 50; and SEQ ID NOs: 51 and52. Nonlimiting exemplary anti-CSF1R antibodies also include antibodiescomprising the following pairs of heavy and light chains: SEQ ID NOs: 33and 34; SEQ ID NOs: 35 and 36; and SEQ ID NOs: 37 and 38.

In some embodiments, an anti-CSF1R antibody comprises heavy chain CDR1,CDR2, and CDR3 of an antibody selected from Fabs 0301, 0302, and 0311.Nonlimiting exemplary anti-CSF1R antibodies include antibodiescomprising sets of heavy chain CDR1, CDR2, and CDR3 selected from: SEQID NOs: 15, 16, and 17; SEQ ID NOs: 21, 22, and 23; and SEQ ID NOs: 27,28, and 29.

In some embodiments, an anti-CSF1R antibody comprises light chain CDR1,CDR2, and CDR3 of an antibody selected from Fabs 0301, 0302, and 0311.Nonlimiting exemplary anti-CSF1R antibodies include antibodiescomprising sets of light chain CDR1, CDR2, and CDR3 selected from: SEQID NOs: 18, 19, and 20; SEQ ID NOs: 24, 25, and 26; and SEQ ID NOs: 30,31, and 32.

In some embodiments, an anti-CSF1R antibody comprises heavy chain CDR1,CDR2, and CDR3, and light chain CDR1, CDR2, and CDR3 of an antibodyselected from Fabs 0301, 0302, and 0311.

Nonlimiting exemplary anti-CSF1R antibodies include antibodiescomprising the sets of heavy chain CDR1, CDR2, and CDR3, and light chainCDR1, CDR2, and CDR3 shown above in Table 1.

Further Exemplary Antibodies

In some embodiments, an anti-CSF1R antibody comprises a heavy chaincomprising a variable region sequence that is at least 90%, at least91%, at least 92%, at least 93%, at least 94%, at least 95%, at least96%, at least 97%, at least 98%, or at least 99% identical to a sequenceselected from SEQ ID NOs: 9, 11, 13, and 39 to 45, wherein the antibodybinds CSF1R. In some embodiments, an anti-CSF1R antibody comprises alight chain comprising a variable region sequence that is at least 90%,at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99% identical to asequence selected from SEQ ID NOs: 10, 12, 14, and 46 to 52, wherein theantibody binds CSF1R. In some embodiments, an anti-CSF1R antibodycomprises a heavy chain comprising a variable region sequence that is atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to a sequence selected from SEQ ID NOs: 9, 11, 13, and 39 to45; and a light chain comprising a variable region sequence that is atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to a sequence selected from SEQ ID NOs: 10, 12, 14, and 46 to52; wherein the antibody binds CSF1R.

In some embodiments, an anti-CSF1R antibody comprises at least one ofthe CDRs discussed herein. That is, in some embodiments, an anti-CSF1Rantibody comprises at least one CDR selected from a heavy chain CDR1discussed herein, a heavy chain CDR2 discussed herein, a heavy chainCDR3 discussed herein, a light chain CDR1 discussed herein, a lightchain CDR2 discussed herein, and a light chain CDR3 discussed herein.Further, in some embodiments, an anti-CSF1R antibody comprises at leastone mutated CDR based on a CDR discussed herein, wherein the mutated CDRcomprises 1, 2, 3, or 4 amino acid substitutions relative to the CDRdiscussed herein. In some embodiments, one or more of the amino acidsubstitutions are conservative amino acid substitutions. One skilled inthe art can select one or more suitable conservative amino acidsubstitutions for a particular CDR sequence, wherein the suitableconservative amino acid substitutions are not predicted to significantlyalter the binding properties of the antibody comprising the mutated CDR.

Exemplary anti-CSF1R antibodies also include antibodies that compete forbinding to CSF1R with an antibody described herein. Thus, in someembodiments, an anti-CSF1R antibody is provided that competes forbinding to CSF1R with an antibody selected from Fabs 0301, 0302, and0311, and bivalent (i.e., having two heavy chains and two light chains)antibody versions of those Fabs.

Exemplary Antibody Constant Regions

In some embodiments, an antibody described herein comprises one or morehuman constant regions. In some embodiments, the human heavy chainconstant region is of an isotype selected from IgA, IgG, and IgD. Insome embodiments, the human light chain constant region is of an isotypeselected from κ and λ. In some embodiments, an antibody described hereincomprises a human IgG constant region. In some embodiments, an antibodydescribed herein comprises a human IgG4 heavy chain constant region. Insome such embodiments, an antibody described herein comprises an S241Pmutation in the human IgG4 constant region. In some embodiments, anantibody described herein comprises a human IgG4 constant region and ahuman κ light chain.

As noted above, whether or not effector function is desirable may dependon the particular method of treatment intended for an antibody. Thus, insome embodiments, when effector function is desirable, an anti-CSF1Rantibody comprising a human IgG1 heavy chain constant region or a humanIgG3 heavy chain constant region is selected. In some embodiments, wheneffector function is not desirable, an anti-CSF1R antibody comprising ahuman IgG4 or IgG2 heavy chain constant region is selected.

Exemplary Anti-CSF1R Heavy Chain Variable Regions

In some embodiments, anti-CSF1R antibody heavy chain variable regionsare provided. In some embodiments, an anti-CSF1R antibody heavy chainvariable region is a mouse variable region, a human variable region, ora humanized variable region.

An anti-CSF1R antibody heavy chain variable region comprises a heavychain CDR1, FR2, CDR2, FR3, and CDR3. In some embodiments, an anti-CSF1Rantibody heavy chain variable region further comprises a heavy chain FR1and/or FR4. Nonlimiting exemplary heavy chain variable regions include,but are not limited to, heavy chain variable regions having an aminoacid sequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45.

In some embodiments, an anti-CSF1R antibody heavy chain variable regioncomprises a CDR1 comprising a sequence selected from SEQ ID NOs: 15, 21,and 27.

In some embodiments, an anti-CSF1R antibody heavy chain variable regioncomprises a CDR2 comprising a sequence selected from SEQ ID NOs: 16, 22,and 28.

In some embodiments, an anti-CSF1R antibody heavy chain variable regioncomprises a CDR3 comprising a sequence selected from SEQ ID NOs: 17, 23,and 29.

Nonlimiting exemplary heavy chain variable regions include, but are notlimited to, heavy chain variable regions comprising sets of CDR1, CDR2,and CDR3 selected from: SEQ ID NOs: 15, 16, and 17; SEQ ID NOs: 21, 22,and 23; and SEQ ID NOs: 27, 28, and 29.

In some embodiments, an anti-CSF1R antibody heavy chain comprises avariable region sequence that is at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% identical to a sequence selected fromSEQ ID NOs: 9, 11, 13, and 39 to 45, wherein the heavy chain, togetherwith a light chain, is capable of forming an antibody that binds CSF1R.

In some embodiments, an anti-CSF1R antibody heavy chain comprises atleast one of the CDRs discussed herein. That is, in some embodiments, ananti-CSF1R antibody heavy chain comprises at least one CDR selected froma heavy chain CDR1 discussed herein, a heavy chain CDR2 discussedherein, and a heavy chain CDR3 discussed herein. Further, in someembodiments, an anti-CSF1R antibody heavy chain comprises at least onemutated CDR based on a CDR discussed herein, wherein the mutated CDRcomprises 1, 2, 3, or 4 amino acid substitutions relative to the CDRdiscussed herein. In some embodiments, one or more of the amino acidsubstitutions are conservative amino acid substitutions. One skilled inthe art can select one or more suitable conservative amino acidsubstitutions for a particular CDR sequence, wherein the suitableconservative amino acid substitutions are not predicted to significantlyalter the binding properties of the heavy chain comprising the mutatedCDR.

In some embodiments, a heavy chain comprises a heavy chain constantregion. In some embodiments, a heavy chain comprises a human heavy chainconstant region. In some embodiments, the human heavy chain constantregion is of an isotype selected from IgA, IgG, and IgD. In someembodiments, the human heavy chain constant region is an IgG constantregion. In some embodiments, a heavy chain comprises a human igG4 heavychain constant region. In some such embodiments, the human IgG4 heavychain constant region comprises an S241P mutation.

In some embodiments, when effector function is desirable, a heavy chaincomprises a human IgG1 or IgG3 heavy chain constant region. In someembodiments, when effector function is less desirable, a heavy chaincomprises a human IgG4 or IgG2 heavy chain constant region.

Exemplary Anti-CSF1R Light Chain Variable Regions

In some embodiments, anti-CSF1R antibody light chain variable regionsare provided. In some embodiments, an anti-CSF1R antibody light chainvariable region is a mouse variable region, a human variable region, ora humanized variable region.

An anti-CSF1R antibody light chain variable region comprises a lightchain CDR1, FR2, CDR2, FR3, and CDR3. In some embodiments, an anti-CSF1Rantibody light chain variable region further comprises a light chain FR1and/or FR4. Nonlimiting exemplary light chain variable regions includelight chain variable regions having an amino acid sequence selected fromSEQ ID NOs: 10, 12, 14, and 46 to 52.

In some embodiments, an anti-CSF1R antibody light chain variable regioncomprises a CDR1 comprising a sequence selected from SEQ ID NOs: 18, 24and 30.

In some embodiments, an anti-CSF1R antibody light chain variable regioncomprises a CDR2 comprising a sequence selected from SEQ ID NOs: 19, 25,and 31.

In some embodiments, an anti-CSF1R antibody light chain variable regioncomprises a CDR3 comprising a sequence selected from SEQ ID NOs: 20, 26,and 32.

Nonlimiting exemplary light chain variable regions include, but are notlimited to, light chain variable regions comprising sets of CDR1, CDR2,and CDR3 selected from: SEQ ID NOs: 18, 19, and 20; SEQ ID NOs: 24, 25,and 26; and SEQ ID NOs: 30, 31, and 32.

In some embodiments, an anti-CSF1R antibody light chain comprises avariable region sequence that is at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% identical to a sequence selected fromSEQ ID NOs: 10, 12, 14, and 46 to 52, wherein the light chain, togetherwith a heavy chain, is capable of forming an antibody that binds CSF1R.

In some embodiments, an anti-CSF1R antibody light chain comprises atleast one of the CDRs discussed herein. That is, in some embodiments, ananti-CSF1R antibody light chain comprises at least one CDR selected froma light chain CDR1 discussed herein, a light chain CDR2 discussedherein, and a light chain CDR3 discussed herein. Further, in someembodiments, an anti-CSF1R antibody light chain comprises at least onemutated CDR based on a CDR discussed herein, wherein the mutated CDRcomprises 1, 2, 3, or 4 amino acid substitutions relative to the CDRdiscussed herein. In some embodiments, one or more of the amino acidsubstitutions are conservative amino acid substitutions. One skilled inthe art can select one or more suitable conservative amino acidsubstitutions for a particular CDR sequence, wherein the suitableconservative amino acid substitutions are not predicted to significantlyalter the binding properties of the light chain comprising the mutatedCDR.

In some embodiments, a light chain comprises a human light chainconstant region. In some embodiments, a human light chain constantregion is selected from a human κ and a human λ light chain constantregion.

Exemplary Additional CSF1R Binding Molecules

In some embodiments, additional molecules that bind CSF1R are provided.Such molecules include, but are not limited to, non-canonical scaffolds,such as anti-calins, adnectins, ankyrin repeats, etc. See, e.g., Hosseet al., Prot. Sci. 15:14 (2006); Fiedler, M. and Skerra, A.,“Non-Antibody Scaffolds,” pp. 467-499 in Handbook of TherapeuticAntibodies, Dubel, S., ed., Wiley-VCH, Weinheim, Germany, 2007.

Exemplary Properties of Anti-CSF1R Antibodies

In some embodiments, an antibody having a structure described abovebinds to the CSF1R with a binding affinity (K_(D)) of less than 1 nM,blocks binding of CSF1 and/or IL-34 to CSF1R, and inhibits CSF1Rphosphorylation induced by CSF1 and/or IL-34.

In some embodiments, an anti-CSF1R antibody binds to the extracellulardomain of CSF1R (CSF1R-ECD). In some embodiments, an anti-CSF1R antibodyhas a binding affinity (K_(D)) for CSF1R of less than 1 nM, less than0.5 nM, less than 0.1 nM, or less than 0.05 nM. In some embodiments, ananti-CSF1R antibody has a K_(D) of between 0.01 and 1 nM, between 0.01and 0.5 nM, between 0.01 and 0.1 nM, between 0.01 and 0.05 nM, orbetween 0.02 and 0.05 nM.

In some embodiments, an anti-CSF1R antibody blocks ligand binding toCSF1R. In some embodiments, an anti-CSF1R antibody blocks binding ofCSF1 to CSF1R. In some embodiments, an anti-CSF1R antibody blocksbinding of IL-34 to CSF1R. In some embodiments, an anti-CSF1R antibodyblocks binding of both CSF1 and IL-34 to CSF1R. In some embodiments, anantibody that blocks ligand binding binds to the extracellular domain ofCSF1R. In some embodiments, an antibody blocks ligand binding to CSF1Rwhen it reduces the amount of detectable binding of a ligand to CSF1R byat least 50%, using the assay described, e.g., U.S. Pat. No. 8,206,715B2, Example 7, which is incorporated herein by reference for anypurpose. In some embodiments, an antibody reduces the amount ofdetectable binding of a ligand to CSF1R by at least 60%, at least 70%,at least 80%, or at least 90%. In some such embodiments, the antibody issaid to block ligand binding by at least 50%, at least 60%, at least70%, etc.

In some embodiments, an anti-CSF1R antibody inhibits ligand-inducedCSF1R phosphorylation. In some embodiments, an anti-CSF1R antibodyinhibits CSF1-induced CSF1R phosphorylation. In some embodiments, ananti-CSF1R antibody inhibits IL-34-induced CSF1R phosphorylation. Insome embodiments, an anti-CSF1R antibody inhibits both CSF1-induced andIL-34-induced CSF1R phosphorylation. In some embodiments, an antibody isconsidered to “inhibit ligand-induced CSF1R phosphorylation” when itreduces the amount of detectable ligand-induced CSF1R phosphorylation byat least 50%, using the assay described, e.g., U.S. Pat. No. 8,206,715B2, Example 6, which is incorporated herein by reference for anypurpose. In some embodiments, an antibody reduces the amount ofdetectable ligand-induced CSF1R phosphorylation by at least 60%, atleast 70%, at least 80%, or at least 90%. In some such embodiments, theantibody is said to inhibit ligand-induced CSF1R phosphorylation by atleast at least 50%, at least 60%, at least 70%, etc.

In some embodiments, an antibody inhibits monocyte proliferation and/orsurvival responses in the presence of CSF1 and/or IL-34. In someembodiments, an antibody is considered to “inhibit monocyteproliferation and/or survival responses” when it reduces the amount ofmonocyte proliferation and/or survival responses in the presence of CSF1and/or IL-34 by at least 50%, using the assay described, e.g., U.S. Pat.No. 8,206,715 B2, Example 10, which is incorporated herein by referencefor any purpose. In some embodiments, an antibody reduces the amount ofmonocyte proliferation and/or survival responses in the presence of CSF1and/or IL-34 by at least 60%, at least 70%, at least 80%, or at least90%. In some such embodiments, the antibody is said to inhibit monocyteproliferation and/or survival responses by at least at least 50%, atleast 60%, at least 70%, etc.

Exemplary Antibody Conjugates

In some embodiments, an antibody is conjugated to a label and/or acytotoxic agent. As used herein, a label is a moiety that facilitatesdetection of the antibody and/or facilitates detection of a molecule towhich the antibody binds. Nonlimiting exemplary labels include, but arenot limited to, radioisotopes, fluorescent groups, enzymatic groups,chemiluminescent groups, biotin, epitope tags, metal-binding tags, etc.One skilled in the art can select a suitable label according to theintended application.

As used herein, a cytotoxic agent is a moiety that reduces theproliferative capacity of one or more cells. A cell has reducedproliferative capacity when the cell becomes less able to proliferate,for example, because the cell undergoes apoptosis or otherwise dies, thecell fails to proceed through the cell cycle and/or fails to divide, thecell differentiates, etc. Nonlimiting exemplary cytotoxic agentsinclude, but are not limited to, radioisotopes, toxins, andchemotherapeutic agents. One skilled in the art can select a suitablecytotoxic according to the intended application.

In some embodiments, a label and/or a cytotoxic agent is conjugated toan antibody using chemical methods in vitro. Nonlimiting exemplarychemical methods of conjugation are known in the art, and includeservices, methods and/or reagents commercially available from, e.g.,Thermo Scientific Life Science Research Produces (formerly Pierce;Rockford, Ill.), Prozyme (Hayward, Calif.), SACRI Antibody Services(Calgary, Canada), AbD Serotec (Raleigh, N.C.), etc. In someembodiments, when a label and/or cytotoxic agent is a polypeptide, thelabel and/or cytotoxic agent can be expressed from the same expressionvector with at least one antibody chain to produce a polypeptidecomprising the label and/or cytotoxic agent fused to an antibody chain.One skilled in the art can select a suitable method for conjugating alabel and/or cytotoxic agent to an antibody according to the intendedapplication.

Exemplary Leader Sequences

In order for some secreted proteins to express and secrete in largequantities, a leader sequence from a heterologous protein may bedesirable. In some embodiments, a leader sequence is selected from SEQID NOs: 3 and 4, which are light chain and heavy chain leader sequences,respectively. In some embodiments, employing heterologous leadersequences may be advantageous in that a resulting mature polypeptide mayremain unaltered as the leader sequence is removed in the ER during thesecretion process. The addition of a heterologous leader sequence may berequired to express and secrete some proteins.

Certain exemplary leader sequence sequences are described, e.g., in theonline Leader sequence Database maintained by the Department ofBiochemistry, National University of Singapore. See Choo et al., BMCBioinformatics, 6: 249 (2005); and PCT Publication No. WO 2006/081430.

Nucleic Acid Molecules Encoding Antibodies

Nucleic acid molecules comprising polynucleotides that encode one ormore chains of an antibody are provided. In some embodiments, a nucleicacid molecule comprises a polynucleotide that encodes a heavy chain or alight chain of an antibody. In some embodiments, a nucleic acid moleculecomprises both a polynucleotide that encodes a heavy chain and apolynucleotide that encodes a light chain, of an antibody. In someembodiments, a first nucleic acid molecule comprises a firstpolynucleotide that encodes a heavy chain and a second nucleic acidmolecule comprises a second polynucleotide that encodes a light chain.

In some such embodiments, the heavy chain and the light chain areexpressed from one nucleic acid molecule, or from two separate nucleicacid molecules, as two separate polypeptides. In some embodiments, suchas when an antibody is an scFv, a single polynucleotide encodes a singlepolypeptide comprising both a heavy chain and a light chain linkedtogether.

In some embodiments, a polynucleotide encoding a heavy chain or lightchain of an antibody comprises a nucleotide sequence that encodes aleader sequence, which, when translated, is located at the N terminus ofthe heavy chain or light chain. As discussed above, the leader sequencemay be the native heavy or light chain leader sequence, or may beanother heterologous leader sequence.

Nucleic acid molecules may be constructed using recombinant DNAtechniques conventional in the art. In some embodiments, a nucleic acidmolecule is an expression vector that is suitable for expression in aselected host cell.

Antibody Expression and Production

Vectors

Vectors comprising polynucleotides that encode antibody heavy chainsand/or light chains are provided. Vectors comprising polynucleotidesthat encode antibody heavy chains and/or light chains are also provided.Such vectors include, but are not limited to, DNA vectors, phagevectors, viral vectors, retroviral vectors, etc. In some embodiments, avector comprises a first polynucleotide sequence encoding a heavy chainand a second polynucleotide sequence encoding a light chain. In someembodiments, the heavy chain and light chain are expressed from thevector as two separate polypeptides. In some embodiments, the heavychain and light chain are expressed as part of a single polypeptide,such as, for example, when the antibody is an scFv.

In some embodiments, a first vector comprises a polynucleotide thatencodes a heavy chain and a second vector comprises a polynucleotidethat encodes a light chain. In some embodiments, the first vector andsecond vector are transfected into host cells in similar amounts (suchas similar molar amounts or similar mass amounts). In some embodiments,a mole- or mass-ratio of between 5:1 and 1:5 of the first vector and thesecond vector is transfected into host cells. In some embodiments, amass ratio of between 1:1 and 1:5 for the vector encoding the heavychain and the vector encoding the light chain is used. In someembodiments, a mass ratio of 1:2 for the vector encoding the heavy chainand the vector encoding the light chain is used.

In some embodiments, a vector is selected that is optimized forexpression of polypeptides in CHO or CHO-derived cells, or in NSO cells.Exemplary such vectors are described, e.g., in Running Deer et al.,Biotechnol. Prog. 20:880-889 (2004).

In some embodiments, a vector is chosen for in vivo expression ofantibody heavy chains and/or antibody light chains in animals, includinghumans. In some such embodiments, expression of the polypeptide is underthe control of a promoter that functions in a tissue-specific manner.For example, liver-specific promoters are described, e.g., in PCTPublication No. WO 2006/076288.

Host Cells

In various embodiments, antibody heavy chains and/or light chains may beexpressed in prokaryotic cells, such as bacterial cells; or ineukaryotic cells, such as fungal cells (such as yeast), plant cells,insect cells, and mammalian cells. Such expression may be carried out,for example, according to procedures known in the art. Exemplaryeukaryotic cells that may be used to express polypeptides include, butare not limited to, COS cells, including COS 7 cells; 293 cells,including 293-6E cells; CHO cells, including CHO—S and DG44 cells;PER.C6® cells (Crucell); and NSO cells. In some embodiments, antibodyheavy chains and/or light chains may be expressed in yeast. See, e.g.,U.S. Publication No. US 2006/0270045 A1. In some embodiments, aparticular eukaryotic host cell is selected based on its ability to makedesired post-translational modifications to the antibody heavy chainsand/or light chains. For example, in some embodiments, CHO cells producepolypeptides that have a higher level of sialylation than the samepolypeptide produced in 293 cells.

Introduction of one or more nucleic acids into a desired host cell maybe accomplished by any method, including but not limited to, calciumphosphate transfection, DEAE-dextran mediated transfection, cationiclipid-mediated transfection, electroporation, transduction, infection,etc. Nonlimiting exemplary methods are described, e.g., in Sambrook etal., Molecular Cloning, A Laboratory Manual, 3^(rd) ed. Cold SpringHarbor Laboratory Press (2001). Nucleic acids may be transiently orstably transfected in the desired host cells, according to any suitablemethod.

In some embodiments, one or more polypeptides may be produced in vivo inan animal that has been engineered or transfected with one or morenucleic acid molecules encoding the polypeptides, according to anysuitable method.

Purification of Antibodies

Antibodies may be purified by any suitable method. Such methods include,but are not limited to, the use of affinity matrices or hydrophobicinteraction chromatography. Suitable affinity ligands include theantigen and ligands that bind antibody constant regions. For example, aProtein A, Protein G, Protein A/G, or an antibody affinity column may beused to bind the constant region and to purify an antibody. Hydrophobicinteractive chromatography, for example, a butyl or phenyl column, mayalso suitable for purifying some polypeptides. Many methods of purifyingpolypeptides are known in the art.

Cell-Free Production of Antibodies

In some embodiments, an antibody is produced in a cell-free system.Nonlimiting exemplary cell-free systems are described, e.g., inSitaraman et al., Methods Mol. Biol. 498: 229-44 (2009); Spirin, TrendsBiotechnol. 22: 538-45 (2004); Endo et al., Biotechnol. Adv. 21: 695-713(2003).

Therapeutic Compositions and Methods

Methods of Treating Pigmented Villonodular Synovitis (PVNS) and OtherConditions

In some embodiments, methods for treating PVNS are provided, comprisingadministering an effective amount of an anti-CSF1R antibody. In someembodiments, the PVNS is diffuse PVNS. In some such embodiments, thePVNS is in a hip and/or knee joint. In some such embodiments, the PVNSis in a hand or foot joint. In some embodiments, methods of treatingother proliferative disorders that involve synovial joints and tendonsheaths, such as giant cell tumor of the tendon sheath (GCTTS) and,tenosynovial giant cell tumor (TGCT) are provided, comprisingadministering an effective amount of an anti-CSF1R antibody. In someembodiments, the antibody is administered at a dose described herein,and for example, at a dose of at least 1, at least 2, at least 4, atleast 8, at least 10, at least 12, at least 16, at least 20, at least30, at least 40, at least 50, or at least 100 mg/kg. In someembodiments, the antibody is administered at a dose described herein,and for example, at a dose of 1 mg/kg, 2 mg/kg, or 4 mg/kg. In someembodiments, the antibody is administered with a frequency describedherein, and for example, once every two weeks, once every three weeks,once every four weeks, once every five weeks, once every six weeks, onceevery eight weeks, or once every ten weeks. In some embodiments, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine, at least ten, at least11, or at least 12 doses may be administered during a course of antibodytreatment.

In some embodiments, treatment of PVNS with an antibody that binds CSF1Rresults in a reduction of tumor volume score of at least 30% or at least40% or at least 50% or at least 60% or at least 70% after at least twoor at least three or at least four doses of the antibody. Tumor volumescore may be measured, for example, using MRI to assess the tumor volumein an affected joint. In some embodiments, the tumor volume score ismeasured in one affected joint. In some embodiments, the tumor volumescore is measured as the total tumor volume in one or more affectedjoints.

The anti-CSF1R antibodies may be administered prior to, concurrentlywith, and/or following at least one additional therapy. Nonlimitingexemplary additional therapies include surgical synovectomy, radiationbeam therapy, radio isotope synovectomy, and joint replacement.

In some embodiments, the anti-CSF1R antibody blocks binding of CSF1and/or IL-34 to CSF1R and/or inhibits CSF1R phosphorylation induced byCSF1 and/or IL-34. In some embodiments, the anti-CSF1R antibody blocksbinding of CSF1 and IL-34 to CSF1R and/or inhibits CSF1R phosphorylationinduced by CSF1 and/or IL-34. In some embodiments, the anti-CSF1Rantibody comprises the CDRs of, or the variable regions of, an antibodyselected from huAb1 to huAb16, described herein. In some embodiments,the anti-CSF1R antibody comprises the CDRs of, or the variable regionsof, huAb1.

Routes of Administration and Carriers

In various embodiments, antibodies may be administered in vivo byvarious routes, including, but not limited to, oral, intra-arterial,parenteral, intranasal, intramuscular, intracardiac, intraventricular,intratracheal, buccal, rectal, intraperitoneal, intradermal, topical,transdermal, and intrathecal, or otherwise by implantation orinhalation. The subject compositions may be formulated into preparationsin solid, semi-solid, liquid, or gaseous forms; including, but notlimited to, tablets, capsules, powders, granules, ointments, solutions,suppositories, enemas, injections, inhalants, and aerosols. A nucleicacid molecule encoding an antibody may be coated onto goldmicroparticles and delivered intradermally by a particle bombardmentdevice, or “gene gun,” as described in the literature (see, e.g., Tanget al., Nature 356:152-154 (1992)). The appropriate formulation androute of administration may be selected according to the intendedapplication.

In various embodiments, compositions comprising antibodies are providedin formulations with a wide variety of pharmaceutically acceptablecarriers (see, e.g., Gennaro, Remington: The Science and Practice ofPharmacy with Facts and Comparisons: Drugfacts Plus, 20^(th) ed. (2003);Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,7^(th) ed., Lippencott Williams and Wilkins (2004); Kibbe et al.,Handbook of Pharmaceutical Excipients, 3^(rd) ed., Pharmaceutical Press(2000)). Various pharmaceutically acceptable carriers, which includevehicles, adjuvants, and diluents, are available. Moreover, variouspharmaceutically acceptable auxiliary substances, such as Ph adjustingand buffering agents, tonicity adjusting agents, stabilizers, wettingagents and the like, are also available. Non-limiting exemplary carriersinclude saline, buffered saline, dextrose, water, glycerol, ethanol, andcombinations thereof.

In various embodiments, compositions comprising antibodies may beformulated for injection, including subcutaneous administration, bydissolving, suspending, or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other oils, synthetic aliphatic acidglycerides, esters of higher aliphatic acids, or propylene glycol; andif desired, with conventional additives such as solubilizers, isotonicagents, suspending agents, emulsifying agents, stabilizers andpreservatives. In various embodiments, the compositions may beformulated for inhalation, for example, using pressurized acceptablepropellants such as dichlorodifluoromethane, propane, nitrogen, and thelike. The compositions may also be formulated, in various embodiments,into sustained release microcapsules, such as with biodegradable ornon-biodegradable polymers. A non-limiting exemplary biodegradableformulation includes poly lactic acid-glycolic acid polymer. Anon-limiting exemplary non-biodegradable formulation includes apolyglycerin fatty acid ester. Certain methods of making suchformulations are described, for example, in EP 1 125 584 A1.

Pharmaceutical packs and kits comprising one or more containers, eachcontaining one or more doses of an antibody or combination of antibodiesare also provided. In some embodiments, a unit dosage is providedwherein the unit dosage contains a predetermined amount of a compositioncomprising an antibody or combination of antibodies, with or without oneor more additional agents. In some embodiments, such a unit dosage issupplied in single-use prefilled syringe for injection. In variousembodiments, the composition contained in the unit dosage may comprisesaline, sucrose, or the like; a buffer, such as phosphate, or the like;and/or be formulated within a stable and effective Ph range.Alternatively, in some embodiments, the composition may be provided as alyophilized powder that may be reconstituted upon addition of anappropriate liquid, for example, sterile water. In some embodiments, thecomposition comprises one or more substances that inhibit proteinaggregation, including, but not limited to, sucrose and arginine. Insome embodiments, a composition of the invention comprises heparinand/or a proteoglycan.

Pharmaceutical compositions are administered in an amount effective fortreatment or prophylaxis of the specific indication. The therapeuticallyeffective amount is typically dependent on the weight of the subjectbeing treated, his or her physical or health condition, theextensiveness of the condition to be treated, or the age of the subjectbeing treated. In general, antibodies may be administered in an amountin the range of about 10 μg/kg body weight to about 100 mg/kg bodyweight per dose. In some embodiments, antibodies may be administered inan amount in the range of about 50 μg/kg body weight to about 5 mg/kgbody weight per dose. In some embodiments, antibodies may beadministered in an amount in the range of about 100 μg/kg body weight toabout 10 mg/kg body weight per dose. In some embodiments, antibodies maybe administered in an amount in the range of about 100 μg/kg body weightto about 20 mg/kg body weight per dose. In some embodiments, antibodiesmay be administered in an amount in the range of about 0.5 mg/kg bodyweight to about 20 mg/kg body weight per dose. In some embodiments,antibodies may be administered at a dose of at least 1, at least 2, atleast 4, at least 8, at least 10, at least 12, at least 16, at least 20,at least 30, at least 40, at least 50, or at least 100 mg/kg. In someembodiments, antibodies may be administered at a dose of 1 mg/kg, 2mg/kg, or 4 mg/kg.

The antibody compositions may be administered as needed to subjects.Determination of the frequency of administration may be made by personsskilled in the art, such as an attending physician based onconsiderations of the condition being treated, age of the subject beingtreated, severity of the condition being treated, general state ofhealth of the subject being treated and the like. In some embodiments,an effective dose of an antibody is administered to a subject one ormore times. In various embodiments, an effective dose of an antibody isadministered to the subject once a month, less than once a month, suchas, for example, every two months or every three months. In otherembodiments, an effective dose of an antibody is administered more thanonce a month, such as, for example, every three weeks, every two weeksor every week. In some embodiments, an effective dose of an antibody isadministered once per 1, 2, 3, 4, or 5 weeks. In some embodiments, aneffective dose of an antibody is administered twice or three times perweek. An effective dose of an antibody is administered to the subject atleast once. In some embodiments, the effective dose of an antibody maybe administered multiple times, including for periods of at least amonth, at least six months, or at least a year.

Combination Therapy

Antibodies may be administered alone or with other modes of treatment.They may be provided before, substantially contemporaneous with, orafter other modes of treatment, for example, surgery, radiation therapy,joint replacement, and/or another therapeutic agent. In someembodiments, the PVNS has recurred or progressed following a therapyselected from surgery, radiation therapy, joint replacement,administration of another therapeutic agent, or a combination thereof.

In some embodiments, the anti-CSF1R antibody is administered before,concurrently, or after at least one treatment selected from surgicalsynovectomy, radiation beam therapy, radio isotope synovectomy, andjoint replacement.

EXAMPLES

The examples discussed below are intended to be purely exemplary of theinvention and should not be considered to limit the invention in anyway. The examples are not intended to represent that the experimentsbelow are all or the only experiments performed. Efforts have been madeto ensure accuracy with respect to numbers used (for example, amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,molecular weight is weight average molecular weight, temperature is indegrees Centigrade, and pressure is at or near atmospheric.

Example 1: Humanized Anti-CSF1R Antibodies

Various humanized anti-CSF1R antibodies were developed previously. See,e.g., PCT Publication No. WO 2011/140249.

The sequences for each of the humanized heavy chain variable regions andhumanized light chain variable regions, aligned with the sequences ofthe parental chimeric antibody variable regions and the sequences of thehuman acceptor variable framework regions are shown in FIGS. 1 (heavychains) and 2 (light chains). The changes in humanized variable regionsequences relative to the human acceptor variable framework regionsequences are boxed. Each of the CDRs for each of the variable regionsis shown in a boxed region, and labeled as “CDR” above the boxedsequences.

Table 8, below, shows the full sequences for the humanized heavy chainsand humanized light chains of antibodies huAb1 to huAb16. The name andSEQ ID Nos of the humanized heavy chain and humanized light chain ofeach of those antibodies is shown in Table

TABLE 3 Humanized heavy chains and light chains of huAb1 to huAb16Humanized Humanized SEQ Humanized SEQ antibody HC ID NO LC ID NO huAb1h0301-H0 53 h0301-L0 60 huAb2 h0301-H1 54 h0301-L0 60 huAb3 h0301-H2 55h0301-L0 60 huAb4 h0301-H0 53 h0301-L1 61 huAb5 h0301-H1 54 h0301-L1 61huAb6 h0301-H2 55 h0301-L1 61 huAb7 h0302-H1 56 h0302-L0 62 huAb8h0302-H1 56 h0302-L1 63 huAb9 h0302-H1 56 h0302-L2 64 huAb10 h0302-H2 57h0302-L0 62 huAb11 h0302-H2 57 h0302-L1 63 huAb12 h0302-H2 57 h0302-L264 huAb13 h0311-H1 58 h0311-L0 65 huAb14 h0311-H1 58 h0311-L1 66 huAb15h0311-H2 59 h0311-L0 65 huAb16 h0311-H2 59 h0311-L1 66

The 16 humanized antibodies were tested for binding to human, cynomolgusmonkey, and mouse CSF1R ECD, as described previously. See, e.g., PCTPublication No. WO 2011/140249. The antibodies were found to bind toboth human and cynomolgus monkey CSF1R ECD, but not to mouse CSF1R ECD.The humanized antibodies were also found to block binding of CSF1 andIL-34 to both human and cynomolgus CSF1R and to inhibit CSF1-induced andIL-34-induced phosphorylation of human CSF1R expressed in CHO cells.See, e.g., PCT Publication No. WO 2011/140249.

The k_(a), k_(d), and K_(D) for binding to human CSF1R ECD werepreviously determined and are shown in Table 4. See, e.g., PCTPublication No. WO 2011/140249.

TABLE 4 Humanized antibody binding affinity for human CSF1R K_(D) huAbk_(a) (M⁻¹s⁻¹) K_(d) (s⁻¹) (Nm) huAb 0301-L0H0 3.22 × 10⁶ 1.11 × 10⁻⁰³0.35 huAb 0301-L0H1 3.56 × 10⁶ 1.22 × 10⁻⁰³ 0.34 huAb 0301-L0H2 2.32 ×10⁶ 6.60 × 10⁻⁰⁴ 0.28 huAb 0301-L1H0 3.29 × 10⁶ 1.15 × 10⁻⁰³ 0.35 huAb0301-L1H1 2.87 × 10⁶ 9.21 × 10⁻⁰⁴ 0.32 huAb 0301-L1H2 2.95 × 10⁶ 7.42 ×10⁻⁰⁴ 0.25 huAb 0302-L0H1 3.54 × 10⁶ 3.69 × 10⁻⁰³ 1.04 huAb 0302-L1H13.47 × 10⁶ 4.04 × 10⁻⁰³ 1.17 huAb 0302-L2H1 1.60 × 10⁶ 9.14 × 10⁻⁰⁴ 0.57huAb 0302-L0H2 3.40 × 10⁶ 1.79 × 10⁻⁰³ 0.53 huAb 0302-L1H2 2.71 × 10⁶1.53 × 10⁻⁰³ 0.56 huAb 0302-L2H2 1.84 × 10⁶ 8.40 × 10⁻⁰⁴ 0.46 huAb0311-L0H1 1.22 × 10⁶ 5.40 × 10⁻⁰⁴ 0.44 huAb 0311-L1H1 1.32 × 10⁶ 6.64 ×10⁻⁰⁴ 0.50 huAb 0311-L0H2 1.34 × 10⁶ 4.73 × 10⁻⁰⁴ 0.35 huAb 0311-L1H21.51 × 10⁶ 6.09 × 10⁻⁰⁴ 0.40

Example 2: Pharmacokinetics and Pharmacodynamics of Anti-CSF1R Antibody

The pharmacokinetics (PK) and toxicokinetics (TK) of huAb1 have beeninvestigated in 3 intravenous (IV) studies in cynomolgus monkeys. Thedose range studied was 3-150 mg/kg after a single dose and 3-150 mg/kgafter repeat doses. The duration of infusion was 30 minutes. The dosinginterval in the repeat-dose studies was once a week with each animalreceiving a total of 4 doses.

The single and repeat-dose PK of a chimeric surrogate antibody wasstudied in SCID mice to help elucidate the mechanism of huAb1 clearanceand better understand the mechanism of the prolonged exposure observedin the monkeys in the recovery group of the GLP toxicology studyrelative to the monkeys in the single-dose PK study.

The PK profile following a single 30-minute IV infusion of huAb1 incynomolgus monkeys was characterized by a rapid distribution, followedby a slower terminal phase that ended with an accelerated depletion ofhuAb1 from the plasma, consistent with target-mediated clearance.

The rapid decrease may be due in part to huAb1 antibodies in addition totarget-mediated clearance. However, a single dose administration of achimeric surrogate antibody in SCID mice, which lack the ability tomount an ADA response, showed a similar profile and supported thecontribution of target-mediated clearance to total clearance of huAb1,especially at low doses.

The observed maximum plasma concentration (Cmax) increasedproportionally to dose at all dose levels tested, while area underplasma concentration-time curve from time zero extrapolated to infinity(AUC∞) increases were greater than dose proportional from 3 mg/kg to 10mg/kg and were dose proportional from 10 mg/kg to 150 mg/kg. Thehalf-life (t½) prior to the accelerated terminal decline ranged from1-12 days and the total clearance ranged from 0.14-1.25 mL/h/kg. Insummary, huAb1 has saturable nonlinear clearance in cynomolgus monkeys.

The effects of huAb1 on various pharmacodynamics (PD) markers known tobe modulated in vivo by CSF1R inhibition were examined in 3 cynomolgusmonkey studies. These markers include CSF1, CD16⁺ monocytes, and boneresorption markers.

CSF1 levels: Plasma or serum levels of CSF1 are a measure of huAb1target engagement. CSF1 is cleared from circulation under normalphysiological conditions by macrophages (primarily splenic macrophagesand liver Kupffer cells) via CSF1R-mediated endocytosis andintracellular degradation. Steady state levels of CSF1 in normalindividuals are <1 μg/ml. huAb1 binds to and prevents CSF1 being clearedby s CSF1R, resulting in a large, rapid increase in circulating CSF1concentration, after which CSF1 levels reach a new steady state ofapproximately 10 μg/ml. In the pilot toxicology study, plasma CSF1 andplasma huAb1 samples were obtained at trough (7 days post-dose)following once-a-week dosing for 4 weeks in cynomolgus monkeys. The datashow that a minimum biological effect occurred at 5 μg/mL huAb1, and ahalf-maximal response (EC₅₀) was 8 μg/mL huAb1.

CD16⁺ monocytes: In the GLP toxicology study, CD16⁺ monocytes werereduced in monkeys receiving 4 weekly IV infusions of 50 mg/kg or 150mg/kg huAb1, consistent with CSF1R pathways supporting the growth andmaintenance of this monocyte subpopulation in vivo. CD16⁺ monocytereduction occurred within 1 week of dosing and was sustained throughoutthe dosing and exposure periods. The CD16⁺ monocytes were restored tonormal baseline levels after huAb1 cleared. The CD16⁻ monocytesubpopulation remained unaffected by administration of huAb1.

Bone resorption markers: Plasma and urine markers of bone resorptionwere evaluated in monkeys following repeat dosing with huAb1. Urine NTx,plasma CTx, and TRAP5b were all decreased. The effects were reversibleupon clearance of huAb1.

Example 3: Treatment of PVNS with an Anti-CSF1R Antibody

huAb1 antibody (an antibody comprising heavy chain and light chainvariable regions of SEQ ID NOs: 53 and 60, respectively) is administeredto patients with PVNS at increasing dosages ranging from 1 mg/kg to 4mg/kg. huAb1 is administered every 2 weeks. Patients are treated in28-day cycles, with each cycle consisting of 2 doses on day 1 and day15. After completing a cycle a patient may be administered an increaseddose in the next cycle.

Patients are monitored for symptomatic improvement and tumor volumescore (TVS). Baseline and post-treatment tumor tissue resections andsynovial fluid may be obtained from patients before and after beginninghuAb1 treatment. Patients are additionally monitored for overallresponse, immune-related response, and overall survival.

MRI tumor assessments are performed within 28 days prior to first doseof huAb1, and then at certain time intervals following the first dose(e.g., 4, 8, 16, and 24 weeks, and every 12-16 thereafter). Clinicalassessment of health outcomes (e.g., function and symptoms) are alsodone every 4 weeks after the first dose. Response to huAb1 is evaluatedusing RECIST for measurable disease.

Patients may be classified according to their best overall tumorresponse (complete response [CR], partial response [PR], stable disease[SD], or progressive disease [PD]). Frequencies, proportions, and exact95% CI of patients, when appropriate, stratified by their best overalltumor response are calculated. Patients with a best overall tumorresponse of CR or PR with duration of at least 4 weeks (28 days) arefurther classified as having an objective tumor response.

Patients will be classified for response by RECIST and the Tumor VolumeScore. The Tumor Volume Score classifies response according to thefollowing definitions: Complete Response [(CR) lesion completely goneafter treatment cycle], Partial Response [(PR)≥50% decrease in volumescore relative to Baseline], Progressive Disease [(PD)≥30% increase involume relative to lowest score during the treatment whether at baselineor some other visit] or Stable Disease [(SD) does not meet any of theprior criteria based on score].

Duration of response is calculated as the number of days from the firstdocumentation of overall response (CR or PR) to the first documentationof disease progression.

Example 4: Summary of a Phase I/II Clinical Trial in Patients withPigmented Villonodular Synovitis (PVNS)/Diffuse Type Tensosynovial GiantCell Tumor (dt-TGCT)

A phase I/II clinical trial is conducted in patients with one or both ofpigmented villonodular synovitis (PVNS) and diffuse type tensynovialgiant cell tumor (dt-TGCT) using huAb1 (also known as FPA008). Theobjective of phase I will be to determine a recommended dose of huAb1 inthe patients, while phase II will be conducted to estimate the objectiveresponse rate (ORR) of huAb1 in the patients. ORR=complete response(CR)+partial response (PR). The study will also characterize the safetyand tolerability of huAb1 in the patients as well as determine theduration of response in responding patients and assess thepharmacokinetics of huAb1 in the patients. In addition, the study willassess the pharmacodynamics of huAb1 as measured by changes in serumlevels of CSF1, IL34, TRAP5b, CTx, and whole blood CD14+/CD16+ monocytesubsets; evaluate synovial biopsies by immunohistochemistry (IHC) forCSF1, CSF1R and CD68; evaluate synovial fluid for huAb1 concentrationand changes in cellularity; and assess functional outcomes as measuredby the Ogilvie-Harris score developed specifically for PVNS(Ogilvie-Harris, 1992; Rhee, 2010) and by the EQ-5D-5L score (Rabin,2001; Herdmann, 2011).

The phase I/II study is open label and patients will be enrolled intoeither phase but not both. Patients are treated with huAb1 every 2 weeksin 28 day cycles. Treatments may be continued after one 28-day cycle.For example, the first dose cycle may be used for a safety andpharmacokinetic assessment, but patients may participate in an extendedtreatment period of, for example, 1, 2, or 3, additional 28-day cyclesor until disease progression (if before 24 weeks), unacceptabletoxicity, patient or physician decision to discontinue, or terminationof the study.

In phase I, 3 patients are enrolled in each of 3 cohorts, the cohortsadministered 1 mg/Kg huAb1, 2 mg/Kg huAb1, or 4 mg/Kg huAb1,respectively. Additional cohorts may be added and an intermediate 3mg/Kg huAb1 cohort may be added. If dose escalation continues higherthan 4 mg/kg, the recommended dose (RD) for phase II may or may not be amaximum tolerated dose (MTD), assuming that an MTD is identified inphase I, but would not be higher than the MTD. The phase II study isbased on the dose selected from the phase I results, or a doseanticipated to be less than or equal to 4 mg/Kg. The phase II dose willbe identified based on overall safety, tolerability, objective response,PK, PD and estimates of efficacious exposures extrapolated fromnonclinical data.

The phase II study duration is 24 weeks and involves 30 patients.

Treated patients are 18 or more years of age and have a histologicallyconfirmed diagnosis of inoperable PVNS/dt-TGCT or potentially resectabletumor that would result in unacceptable functional loss or morbidity asdetermined by a qualified surgeon or multi-disciplinary tumor board.Patients may have measurable PVNS/dt-TGCT by RECIST 1.1 on MRI.

Treated patients have not received prior therapy with an anti-CSF1Rantibody or with PLX3397 unless discontinued for intolerance. Patientsmay have received prior therapy with imatinib or nilotinib, however.Patients have not had any surgical procedure of the involved jointwithin 12 weeks prior to first study dose administration.

Pharmacokinetic parameters will be assessed in the patients. Thefollowing PK parameters will be derived from concentration-time data forFPA008, when appropriate and applicable (other parameters, such asaccumulation ratio and half-life, may also be calculated): Area underserum concentration-time curve (AUC); Maximum serum concentration(C_(max)); Minimum serum concentration (C_(min)); Clearance (CL); Volumeof distribution at steady state (V_(ss)).

Pharmacodynamic (PD) parameters are also assessed: Serum—CSF1 and IL34ligand concentration, CTx, and TRAP5b bone resorption markerconcentrations; Whole blood—CD14⁺/CD16⁺ monocyte subsets; Synovium(optional)—evaluate synovial biopsy for CSF1 gene translocation (if notpreviously done), baseline and on treatment synovial biopsy, IHC for:CSF1 and CSF1R and/or for CD68; Synovial fluid (optional)—huAb1concentration; cellular component for above markers by IHC.

Immunogenicity is assessed, for example, by collecting blood samples andassaying samples for anti-drug antibodies to huAb1.

Responsiveness is assessed, for example, by the following: MRI ofaffected joints will be performed at Screening, 4, 8, and 16 weeks (oruntil treatment discontinuation) following the start of treatment.Response per MRI will be assessed using RECIST 1.1 and TVS based onindependent central radiology review. In addition, if there is a goodtumor response rate, changes in surrounding bone and other joint tissuesmay be evaluated based on the whole organ MRI score (WORMS) andrheumatoid arthritis MRI score (RAMRIS). Clinical assessment of healthoutcomes (function, symptoms) will be done at Screening, C1D15(pre-dose), C2D1 (pre-dose), and then on Day 1 (pre-dose) for allsubsequent cycles through 24 weeks or until treatment is discontinued.Patients who have not progressed at Treatment Completion/EarlyTermination and agree to continue participation in the study are to befollowed (MRI and assessment of health outcomes) every 14 (±2) weeksuntil progression, the patient undergoes local therapy (e.g., resection,radiation) or a new systemic therapy is initiated, for up to 52 weeksfollowing C1D1.

Safety is assessed by monitoring adverse events and changes in physicalexaminations, vital signs, 12-lead ECGs, and clinical laboratorymeasurements.

All analyses will be descriptive and will be presented by dose group andoverall as appropriate. Patient data from the Phase 2 will be summarizedas a separate group. All patients dosed at the RD will also besummarized. Because of the low number of patients that may be enrolledat lower dose levels, some dose levels may be combined forsummarization. Missing values in the efficacy data will be treated asmissing; no efficacy data will be imputed.

Data collected in this study will be presented using summary tables andpatient data listings. Continuous variables will be summarized usingdescriptive statistics, specifically the mean, median, standarddeviation (SD), minimum, and maximum. Categorical variables will besummarized by frequencies and percentages. 95% confidence intervals willbe presented where appropriate. Response rates and the correspondingconfidence interval (CI) will be used to access efficacy. It isanticipated that there will a total of approximately 33 to 36 patientstreated at the RD overall. Table 6 displays the corresponding 95%confidence interval and the precision for various sample sizes andobserved response rates. PK parameters will be calculated usingnon-compartmental analysis methods, though compartmental analysismethods may be employed if appropriate.

Example 5: Phase I/II Clinical Trial in Patients with PigmentedVillonodular Synovitis (PVNS)/Diffuse Type Tensosynovial Giant CellTumor (dt-TGCT) 1. Introduction 1.1. PVNS Background

Pigmented villonodular synovitis (PVNS) is a benign neoplasm of thesynovium with features of both reactive inflammation and clonalneoplastic proliferation in which colony stimulating factor-1 (CSF1) isover expressed. A common translocation of the CSF1 gene (1p13) to theCOL6A3 promoter (2q35) is present in approximately 60% of PVNS patients.The translocation is accompanied by CSF1 overexpression in the synovium.In addition, approximately 40% of PVNS patients have CSF1 overexpressionin the absence of an identified CSF1 translocation. The consistentpresence of CSF1 overexpression in all cases of PVNS and reactivesynovitis suggests both an important role for CSF1 in the spectrum ofsynovial pathologies and the utility of targeting the CSF1/CSF1Rinteraction therapeutically (West, 2006).

In PVNS, CSF1 overexpression is present in a minority of synovial cells,whereas the majority of the cellular infiltrate expresses CSF1R but notCSF1. This has been characterized as a tumor-landscaping effect withaberrant CSF1 expression in the neoplastic cells, leading to theabnormal accumulation of non-neoplastic cells that form a mass.

Surgery is the treatment of choice for patients with localized PVNS.Recurrences occur in 8-20% of patients and are easily managed byre-excision. PVNS/dt-TGCT tends to recur more often (33-50%) and has amuch more aggressive clinical course. Patients are often symptomatic andrequire multiple surgical procedures during their lifetime. For patientswith unresectable disease or multiple recurrences, systemic therapyusing CSF1R inhibitors may help delay or avoid surgical procedures andimprove functional outcomes (Ravi, 2011).

Imatinib, a non-specific inhibitor of CSF1R, has undergone evaluation in29 PVNS patients. The median age was 41 years and the most common siteof disease was the knee (n=17; 59%). Five of 27 evaluable patients hadcomplete (n=1) or partial (n=4) responses per RECIST for an overallresponse rate of 19%. Twenty of 27 patients (74%) had stable disease.Symptomatic improvement was noted in 16 of 22 patients (73%) who wereassessable for symptoms. Despite a high rate of symptomatic improvementand an overall favorable safety profile, 10 patients discontinuedtreatment for either toxicity or other reasons (Cassier, 2012).

Recently two studies of potent inhibitors of CSF1 signaling have shownpreliminary but compelling clinical activity in patients with PVNS.PLX3397, a CSF1R kinase inhibitor, and RG7155, a monoclonal antibodytargeting CSF1R have been evaluated in patients with PVNS (Cassier,2014; Tap, 2014). In both studies, a majority of patients with PVNSresponded to treatment based on RECIST, FDG-PET, and/or total volumescore, which is a measure of disease volume by MRI.

In PVNS, overexpression of CSF1 by a minority of cells leads torecruitment of CSF1R-expressing cells that make up the bulk of the tumormass. FPA008 antagonizes CSF1R activation and should result in thereduction of CSF1R-expressing cells in the tumor thereby providingclinical benefit.

1.2. FPA008: Description of the Molecule

HuAB1, also called FPA008, is a humanized IgG4 monoclonal antibody witha single amino acid substitution in the hinge region to preventhemi-dimer exchange. FPA008 has high affinity binding to human colonystimulating factor 1 receptor (CSF1R), a receptor tyrosine kinase.

1.2.1. Nonclinical Studies with FPA008

1.2.1.1. FPA008 Inhibition of CSF1R Signaling

FPA008 inhibited both CSF1 and IL34-induced CSF1R phosphorylation in acell line engineered to overexpress CSF1R (CHO-CSF1R), demonstratingFPA008 blocks the activation of ligand-induced CSF1R signaling pathways.FPA008 also inhibits CSF1 and IL34-induced proliferation/survival ofperipheral blood monocytes in vitro, demonstrating FPA008 inhibits notonly the initiation of CSF1 and IL34 signaling pathways, but also thesubsequent physiologic responses of primary human monocytes to theseligands (for further details, see the FPA008 Investigator's Brochure[IB]).

1.2.2. Nonclinical Pharmacokinetics and Pharmacodynamics 1.2.2.1.Pharmacokinetics

The pharmacokinetics (PK) and toxicokinetics (TK) of FPA008 have beeninvestigated in 4 intravenous (IV) studies in cynomolgus monkeys. Thedose range studied was 3-150 mg/kg after a single intravenous bolus doseand 3-150 mg/kg after repeat intravenous infusion doses. The duration ofinfusion was 30 minutes. The dosing interval in the repeat-dose studieswas once a week with each animal receiving a total of 4 doses in twostudies and 13 doses in one study.

The PK profile following a single IV bolus administration of FPA008 incynomolgus monkeys was characterized by a rapid distribution, followedby a slower terminal phase that ended with an accelerated depletion ofFPA008 from the plasma, consistent with target-mediated clearance.

The rapid decrease may be due in part to anti-FPA008 antibodies inaddition to target-mediated clearance. However, a single doseadministration of cmFPA008 in SCID mice, which lack the ability to mountan ADA response, showed a similar profile and supported the contributionof target-mediated clearance to total clearance of FPA008, especially atlow doses.

The observed maximum plasma concentration (C_(max)) increasedproportionally to dose at all dose levels tested, while area underplasma concentration-time curve from time zero extrapolated to infinity(AUC_(∞)) increases were greater than dose proportional from 3 mg/kg to10 mg/kg and were dose proportional from 10 mg/kg to 150 mg/kg. Thehalf-life (t_(1/2)) prior to the accelerated terminal decline rangedfrom 1-12 days and the total clearance ranged from 0.14-1.25 mL/h/kg. Insummary, FPA008 has saturable target-mediated clearance in cynomolgusmonkeys.

1.2.2.2. Pharmacodynamics

The effects of FPA008 on various pharmacodynamics (PD) markers known tobe modulated in vivo by CSF1R inhibition were examined in 3 cynomolgusmonkey studies (details are provided in Section 5.1.1.7 of the IB).These markers include CSF1, CD16⁺ monocytes, and bone resorptionmarkers. IL34 was not measured in monkeys due to lack of an appropriateassay.

CSF1 levels: Plasma or serum levels of CSF1 are a measure of FPA008target engagement. CSF1 is cleared from circulation under normalphysiological conditions by macrophages (primarily splenic macrophagesand liver Kupffer cells) via CSF1R-mediated endocytosis andintracellular degradation (Bartocci, 1987). Steady state levels of CSF1in normal individuals are <1 ng/ml. FPA008 binds to and prevents CSF1being cleared by CSF1R, resulting in a large, rapid increase incirculating CSF1 concentration, after which CSF1 levels reach a newsteady state of approximately 10 μg/ml. In the pilot toxicology study,plasma CSF1 and plasma FPA008 samples were obtained at trough (7 dayspost-dose) following once-a-week dosing for 4 weeks in cynomolgusmonkeys. The data show that a minimum biological effect occurred at 5μg/mL FPA008, and a half-maximal response (EC₅₀) was 8 μg/mL FPA008.While FPA008 elevates CSF1, FivePrime believes that these elevationswill have no consequence because:

-   -   CSF1R is the only identified receptor through which CSF1 signals        and this is antagonized by FPA008.    -   The levels of CSF1 fall concomitantly with the clearance of        FPA008.    -   In the presence of FPA008, when CSF1 is elevated, the potential        for extremely high concentrations of CSF1 to displace FPA008        from the CSF1R receptor was evaluated in the FPA008 cell potency        assay. The data showed that concentrations as high as 10 μg/mL        CSF1 had no impact on FPA008 potency or maximal inhibition of        CSF1R signaling.    -   No rebound increase in CD16⁺ monocytes was observed once FPA008        is cleared in preclinical in vivo studies.

CD16⁺ monocytes: In the GLP toxicology study, CD16⁺ monocytes werereduced in monkeys receiving 4 weekly IV infusions of 50 mg/kg or 150mg/kg FPA008, consistent with CSF1R pathways being necessary to supportthe growth and maintenance of this monocyte subpopulation in vivo. CD16⁺monocyte reduction occurred within 1 week of dosing and was sustainedthroughout the dosing and exposure periods. The CD16⁺ monocytes wererestored to normal baseline levels after FPA008 cleared. The CD16⁻monocyte subpopulation remained unaffected by administration of FPA008.

Bone resorption markers: Plasma and urine markers of bone resorptionwere evaluated in monkeys following repeat dosing with FPA008. UrineNTX, plasma CTx, and TRAP5b were all decreased. The effects werereversible upon clearance of FPA008.

1.2.3. Nonclinical Toxicology Studies and Findings

Full details of the nonclinical toxicology studies are provided inSection 5.3 of the IB. All toxicity studies were performed in cynomolgusmonkey since FPA008 is not cross-reactive to rodents but shows similarin vitro binding affinity to cynomolgus monkey and human CSF1R andsimilar tissue binding profile in a tissue cross reactivity studycomparing a panel of human and cynomolgus monkey tissues. Fournonclinical in vivo toxicology studies were performed using FPA008: Asingle-dose pharmacokinetic (PK)/tolerability study with doses of 3, 10,30, and 150 mg/kg, a dose range finding repeat-dose toxicity study with4 weekly IV doses of 3, 10, and 150 mg/kg, a repeat-dose GLP toxicitystudy with 4 weekly IV doses of 50 mg/kg and 150 mg/kg and a 30 weekrecovery phase, and a subchronic repeat-dose GLP toxicity study with 13weekly IV doses of 20, 50, and 100 mg/kg and a 29-week recovery phase.

In the in vivo toxicology studies in cynomolgus monkeys, FPA008 wasgenerally well tolerated. Test article-related findings includedclinical observations, hematology and clinical chemistry changes, andhistologic changes. The majority of these observations were considerednon-adverse.

1.2.3.1. Periorbital Edema

The most prominent physical finding was reversible periorbital edema,seen after prolonged exposure to FPA008. The onset of the edema did notshow a clear relationship to exposure levels, however edema resolvedafter systemic clearance of the drug. Periorbital edema is a known sideeffect with drugs affecting the CSF1 pathway (Ries, 2014).

1.2.3.2. Monocyte Depletion

The main hematologic change was a decrease in circulating CD16⁺monocytes, which was considered a pharmacodynamic (PD) effect. Thedecreased cell numbers normalized with clearance of FPA008 fromcirculation.

1.2.3.3. Enzyme Elevations

FPA008-related clinical chemistry effects included reversible increasedalanine transaminase (ALT), aspartate transaminase (AST), and creatinekinase (CK) serum levels. These laboratory abnormalities were notassociated with any histopathological evidence of liver, cardiac, ormuscle tissue injury at terminal or recovery necropsy. Cardiac troponin,skeletal troponin, myoglobin, and aldolase were also measured during thein-life portion of the study, and no changes were detected in any ofthese parameters further confirming the lack of any liver or muscleinjury. The increased serum levels are attributed to diminishedclearance of the ALT, AST, and CK molecules from serum due to a reducednumber of liver Kupffer cells (Radi, 2011). Accordingly, the ALT, AST,and CK elevations are considered non-toxic and an indirect PD effect ofFPA008 exposure.

1.2.3.4. Accumulation of Extracellular Matrix

The most noteworthy histopathological finding in both pivotal studies atterminal necropsy was the observation of reversible expansion of thesubmucosal collagen fibers by clear space and varying amounts of a blue,granular extracellular matrix (ECM). This finding was present in a largevariety of tissues and was generally minimal to mild in severity. It wasmost prominently seen in the esophagus. This change was not associatedwith inflammatory cells or with any sign of degeneration or otheralteration of the collagen fibers, fibroblasts, or the smooth musclecells within the area of expansion. A similar observation was also notedin op/op mice that lack functional CSF1 (Radi, 2009). In thispublication, the authors postulated that the reduction of tissuemacrophages likely causes the observed accumulation of ECM due to adecreased clearance of glycosaminoglycans by macrophages.Glycosaminoglycans, especially hyaluronic acid, are prominent inconnective tissue and are normally catabolized by macrophages (Radi,2009). This change is considered to be an indirect PD effect of FPA008.There was no evidence that the accumulation of the blue granular ECM wasadverse; there were no associated clinical observations or organ weightchanges that correlated to the histopathologic observations. Inaddition, these changes in the ECM were reversible during a drug-freerecovery period, and therefore, were considered non-adverse.

1.2.3.5. Other Findings

Unique to the 4-week GLP study was a finding in a single female dosedwith 150 mg/kg. At terminal sacrifice microscopic evidence of mildinflammation of the epicardium and vacuolation of cardiac myocytes wasseen. The significance of this finding is unknown, but association withFPA008 cannot be excluded. Chronic, mild epicardial inflammation can bea background lesion in nonhuman primates. However, vacuolation of a cellcan be an early sign of a non-specific, cellular response to injuriousstimuli. Vacuolation of myocytes was not found in any of the other dosedanimals. It is important to note that this vacuolation did not lead todegeneration or necrosis, and did not cause changes in recorded ECGs. Nocardiac changes were detected in any animals at recovery or in the13-week toxicity study. This event was considered an adverse finding inthe 4-week toxicity study.

Also unique to the 4-week study was increased spleen organ weights withcorresponding histopathological findings of minimal to mild follicularhyperplasia in female animals. The finding was considered of lowtoxicological significance and non-adverse, and no spleen hyperplasiawas seen in the 13-week toxicity study.

As macrophages engulf pathogens to destroy them (Dale, 2008), treatmentwith FPA008 may be associated with an increased risk of susceptibilityto intracellular pathogens such as Mycobacterium tuberculosis, Listeriamonocytogenes, Leishmania, and others. While no spontaneous infectionshave been noted in FPA008 animal studies to date, clinical studyprotocols will contain exclusion criteria for those patients at greatestrisk. Patients will be monitored regularly for adverse events andinfections while on study.

1.2.3.6. Summary

The no-observable-adverse-effect level (NOAEL) for FPA008 was determinedto be 100 mg/kg when administered for 13 weekly doses to cynomolgusmonkeys.

1.3. Clinical Experience with FPA008

FPA008 is currently being evaluated in a double-blind, randomized,placebo-controlled first-in-human trial designed in 3 parts to studysafety, pharmacokinetics (PK), and PD biomarkers. In Part 1, 8 healthyvolunteers were randomized (3:1) to receive a single intravenousinfusion of FPA008 or placebo, per dose cohort of 0.2, 1, 3, or 10mg/kg. In Part 2, 8 healthy volunteers were randomized (3:1) to receive2 doses of FPA008 or placebo administered 14 days apart, at 1 mg/kg or 3mg/kg. Dose escalation decisions were based on the incidence of doselimiting toxicities (DLTs) plus attributed adverse events beyond the DLTperiod. Part 3 consists of an open-label evaluation of 3 dose levels inRA patients whose disease is not responding to disease modifyinganti-rheumatic drugs (DMARDs) and on a stable dose of methotrexate.Three subjects per dose level will receive 2 doses of FPA008administered intravenously 14 days apart in the open-label part.Thereafter, 30 new subjects will be randomized (2:2:1) to one of twodose levels of FPA008 or placebo, respectively, and receive 3 dosesadministered intravenously every 14 days. No clinical safety data areyet available for Part 3 patients.

Forty-eight healthy volunteers completed Parts 1 and 2 of the study; 36of these subjects received FPA008 and 12 received placebo. FPA008 waswell tolerated in healthy volunteers up to 3 mg/kg dual doses. The mostcommon FPA008 treatment-related toxicities were pruritus, eyelid edemaalong with facial swelling, fatigue, and headache. The events were Grade1 or 2, and self-limited. At 10 mg/kg, all 6 active subjects experiencedmoderate (Grade 2) eyelid edema or facial swelling, some accompaniedwith swelling in hands and feet, blurry vision, and weight gain. Theevents lasted up to 3 months and coincided with prolonged PK exposure atthis dose level. No adverse events met protocol definitions fordose-limiting toxicities.

Dose-dependent elevations of CK up to 6.8 times the upper limit ofnormal and lactate dehydrogenase (LDH) up to 2.2 times the upper limitof normal were noted at 1 mg/kg and above; AST elevation up to 2.1 timesthe upper limit of normal occurred at 3 mg/kg and above and occurred ina greater percentage of volunteers with increasing dose; and mild ALTelevation up to 1.2 times the upper limit of normal occurred at 10 mg/kgin 1 subject. Peak values occurred 2-8 weeks following drugadministration, typically with normalization by 12 weeks. Theseelevations were not associated with clinical signs/symptoms orabnormalities in total bilirubin, CK isoenzymes, or troponin. They werereversible and were expected due to FPA008-mediated inhibition ofKupffer cells responsible for their clearance (Radi, 2011) and areconsidered to be a pharmacologic effect of inhibiting CSF1R rather thanrepresenting tissue injury.

The adverse event profile observed in this study is relatively similarto what has been reported in other compounds targeting the CSF1R pathway(Cassier, 2014; Tap, 2014).

FPA008 exhibited saturable target-mediated clearance in the dose rangetested. The PK characteristics observed in healthy volunteers supportdosing of FPA008 once every 2 weeks or less frequently to maintaindesired drug exposure. Reduction of CD16⁺ monocytes, decreased boneturnover biomarkers (CTx, TRAP5b), and dose-dependent increase in serumCSF1 and IL34 concentrations were observed.

1.4. Risk-Benefit Assessment

The safety, PK, and PD of FPA008 in healthy volunteers were generallypredicted based on the nonclinical toxicology studies of FPA008. Moredetails on the toxicology studies are provided in the D3.

In the nonclinical toxicology studies, FPA008 was well tolerated inanimals at high doses up to 100 mg/kg for up to 13 weekly doses. PDeffects (CSF1 and CD16⁺ monocytes) occurred at drug exposure levels wellbelow those associated with adverse events or abnormal laboratoryfindings.

Evidence from mouse models to evaluate potential risk ofpharmacologically mediated toxicity associated with interruption of CSF1and IL34 signaling has shown that the deletion of CSF1, IL34, or CSF1Ris non-lethal. Mice deficient in CSF1 show a loss of bone osteoclastsand display deficiency in some myeloid cells at birth (Yoshida, 1990);mice deficient in IL34 lack Langerhans cells in the epidermis andmicroglia in some areas of the brain (Wang, 2012; Greter, 2012); andmice deficient in CSF1R display both osteoporosis and deficiency ofLangerhans cells and microglia (Hamilton, 2013).

Binding of FPA008 to CSF1R does not produce an agonist effect asdemonstrated by experiments conducted at FivePrime (details provided inthe IB). Additionally, FPA008 is an IgG4 antibody, and in vitro testinghas confirmed that it has no specific antibody-dependent cell-mediatedcytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity.

Although PVNS is managed by local intervention in most patients, somepatients present with or have chronic or recurrent disease that is notwell managed by surgery or other available therapies. Imatinib iseffective in a minority of patients but has some on-target andoff-target toxicities that limit its usefulness. Preliminary reports ofspecific CSF1R inhibitors suggest that FPA008 may be a beneficialtreatment for non-surgical PVNS, which can be a debilitating disease.

2. Study Objectives and Endpoints 2.1. Primary Objective

Phase 1: To determine the recommended dose (RD) of FPA008 in patientswith PVNS/dt-TGCT

Phase 2: To estimate the objective response rate (ORR=CR+PR) of FPA008in patients with PVNS/dt-TGCT

2.2. Secondary Objectives

To characterize the safety and tolerability of FPA008 in patients withPVNS/dt-TGCT

To determine the duration of response in responding patients

To assess the pharmacokinetics of FPA008 in patients with PVNS/dt-TGCT

2.3. Exploratory Objective

To assess the pharmacodynamics of FPA008 as measured by changes in serumlevels of CSF1, IL34, TRAP5b, CTx, and whole blood CD14⁺/CD16⁺ monocytesubsets

To evaluate synovial biopsies by immunohistochemistry (IHC) for CSF1,CSF1R and CD68 markers in selected patients

To evaluate synovial fluid for FPA008 concentration and changes incellularity in selected patients

To assess functional outcomes as measured by the Ogilvie-Harris scoredeveloped specifically for PVNS and by the EQ-5D-5L score

2.4. Primary Study Endpoints

Phase 1: The incidence of Grade 3 and Grade 4 adverse events (AEs) andclinical laboratory abnormalities defined as dose-limiting toxicities(DLTs)

Phase 2: The incidence of confirmed objective responses per RECIST 1.1

2.5. Secondary Endpoints

PK Parameters

The incidence of AEs, clinical laboratory abnormalities, and ECGabnormalities

Duration of response per RECIST 1.1

2.6. Exploratory Endpoints

PD Parameters

Symptom and Functional Outcomes as measured by the Ogilvie-Harris scoredeveloped specifically for PVNS and by the EQ-5D-5L score

3. Overall Design and Plan of the Study 3.1. Overview

This is a Phase 1/2 study. Phase 1 is a dose escalation, open-label,safety, tolerability, PK, and PD study of FPA008. Patients will beenrolled into either Phase 1 or Phase 2 of the study, but not both.

Enrolled patients will be treated in 28-day cycles. Each cycle willconsist of 2 doses: on Day 1 and Day 15.

3.1.1. Screening Period

All Screening evaluations must be completed and reviewed by theInvestigator and Medical Monitor to confirm that patients meet alleligibility criteria before the first infusion of FPA008 (Appendix 1).Written informed consent for participation in the study must be obtainedbefore performing any study specific Screening tests or procedures.Screening assessments will be performed within 28 days prior to thefirst dose of FPA008 unless otherwise specified.

Study-procedure-related AEs that occur after signing of the informedconsent form and before administration of the first FPA008 dose will becollected during this period.

3.1.2. Phase 1 (Dose Escalation)

Dose escalation will continue until either the MTD or maximum feasibledose is reached, with a minimum of 3 patients enrolled in each cohort.The anticipated dose levels and schedules are: Dose level 1: 1 mg/kgq2w; Dose level 2: 2 mg/kg q2w; Dose level 3: 4 mg/kg q2w.

All dose escalation decisions will be based on assessment of DLTs,overall safety, and tolerability and will be made after the last patientenrolled in each cohort has completed the first treatment cycle. Doseescalation decisions will be agreed upon between the Investigators andthe Sponsor. Prior to initiating each new dose level or expanding anexisting dose level, a safety teleconference will be held whereinInvestigators and the Sponsor review patient data, including, but notlimited to, demographics, FPA008 dosing, concomitant medications,hematology and serum chemistry, and AEs; and confer and documentagreement that dose escalation or expanding an existing dose level isconsidered appropriate. If the Sponsor and Investigators collectivelyagree that following review of safety and pharmacokinetic data, that adifferent dose escalation scheme should be used than the one outlined,this will be permitted. Review of safety, PK and PD parameters mayinform decisions to add cohorts with alternative dose levels or doseregimens (e.g., less frequent dosing or with a loading dose) in order toreach an optimal target exposure.

The following algorithm will be used for dose escalation decisions:

TABLE 1 Dose-Escalation Considerations Number of Patients with DLT at aGiven Dose Level Dose Escalation Decision Rule  0/3 Escalation willoccur to the next higher dose cohort  1/3 Enroll three more patients insame cohort ≥2/3 Stop enrollment. Enter three more patients at doselevel below, if only three were previously entered  1/6 Open next cohort≥2/6 Stop enrollment. Enter 3 more patients at a dose level below or atan intermediate dose level if the current dose level is ≥50% higher thanthe previous dose level in the same manner as described above.

The MTD is defined as the highest dose associated with DLTs in less than33% of patients receiving FPA008 administered on Days 1 and 15 of a28-day cycle. This will normally be the dose recommended for furtherstudy (RD); however, based on review of safety and PK data, the RD couldbe lower than the MTD. If the MTD is not reached, and the highestevaluated FPA008 dose is well tolerated, the data will be reviewed toassess whether further dose escalations are warranted. The protocol maybe amended if additional dose escalation is considered appropriate.

If the MTD is not reached during Phase 1, or subsequent cycles oftreatment in Phase 1 provide additional insight on the safety profile,an RD may be selected based on overall tolerability, safety, and PK.

If a patient does not receive 2 doses and does not complete the safetyand PK assessment in Cycle 1 for reasons other than toxicity (e.g.,disease progression or withdrawal of consent), then an additionalpatient will be enrolled into the cohort so that the cohort has at leastthree patients evaluable for tolerability through Cycle 1. All suchdiscussions and decisions will be documented as part of the doseescalation decision-making process.

Intra-patient dose escalation above the starting dose for each patientis not permitted.

If a patient's dose is decreased for an adverse event, dose escalationto the originally assigned dose may occur after resolution of the AE andafter discussion with and approval by the Sponsor. Recurrence of the AEto greater than Grade 2 will result in permanent dose reduction withoutthe opportunity for re-escalation.

On completion of Cycle 1 (Safety and PK Assessment Period), Phase 1patients may participate in an Extended Treatment Period, which beginson Day 1 of Cycle 2. FPA008 will be administered every 2 weeks in 4-weekcycles for up to 24 weeks or until disease progression (if before 24weeks), unacceptable toxicity, patient or physician decision todiscontinue, death, or Sponsor termination of the study, assuming nolimitations with availability of drug supply, or other issues that maypreclude the Sponsor from providing FPA008.

3.1.3. Phase 2

Enrollment in Phase 2 will begin when the RD has been identified by theCRC, based on overall safety, tolerability, objective response, PK, PDand estimates of efficacious exposures extrapolated from nonclinicaldata. The RD is anticipated to be ≤4 mg/kg. However, it is possible thatPVNS/dt-TGCT patients may have different drug exposure relative tohealthy volunteers. If dose escalation continues higher than 4 mg/kg,the RD may or may not be an MTD, if an MTD is identified in Phase 1. Forexample, if an MTD is not reached, or if exposure at the MTD is muchhigher than the level believed to be required for efficacy, or ifsubsequent cycles of treatment provide additional insight on the safetyprofile, then the RD may be a different, though not higher, dose thanthe MTD.

Treatment is planned to continue every 2 weeks for up to 24 weeks (nomore than 12 doses) or until disease progression.

If a patient appears to have stable or improving symptoms with stablemeasurable disease or better by MRI, but is having intolerable or Grade3 or greater adverse events, dose reduction by 25-50% may be allowedwith Sponsor agreement.

3.2. Procedures

Patients will undergo safety evaluations (DLTs and other AEs, vitalsigns, ECGs, clinical laboratory tests), determination of ECOGperformance status (PS), and physical examinations (Appendix 1).Additionally, blood samples will be collected for PK and PD analyses forall patients (Appendix 2).

MRI of affected joints will be performed at Screening, 4, 8, and 16weeks following the start of treatment. An MRI should also be performedat the 30 days (±7 days) and 90 days (±7 days) End of TreatmentFollow-up Visits unless already performed within the previous 6 weeks orif tumor progression was previously determined. Patients who have notprogressed and enter Long-Term Follow-up should have MRI every 14 (±2)weeks until progression, the patient undergoes local therapy (e.g.,resection, radiation) or a new systemic therapy is initiated, for up to52 weeks following C1D1. Response per MRI will be assessed using RECIST1.1 and TVS based on independent central radiology review.

Clinical assessment of health outcomes (function, symptoms) will be doneevery 4 weeks after the first administration of study drug.

Safety will be assessed by monitoring AEs and changes in physicalexaminations, weight, vital signs, 12-lead ECGs, and laboratorymeasurements. Assessment of AEs will follow the guidelines provided inthe National Cancer Institute (NCI)—Common Terminology Criteria forAdverse Events (CTCAE), version 4.03. Blood samples will also be drawnat scheduled time points (Appendix 2) during the study for determinationof drug serum concentration, and anti-drug antibodies (ADAs) (i.e.,antibody response to FPA008).

In patients who have archival tumor tissue available and who have signedthe Optional Research Sample Informed Consent Form, the tissue will beevaluated for CSF1 gene translocation if not previously done (Appendix1). In addition, CSF1 and CSF1R and CD68 markers and will be determined.

For patients who sign the applicable Optional Research Sample InformedConsent Form, baseline tumor tissue resections (≥0.5 cm to ≤2 cm) andsynovial fluid (if applicable) will be obtained from patients prior tostarting FPA008 treatment and after eligibility criteria have beenfulfilled. The baseline tissue sample will be reviewed by a pathologistto determine whether the tissue is evaluable. If the Screening tissuesample is evaluable, a subsequent biopsy will be performed before theCycle 2, Day 1 administration of FPA008 (Appendix 1).

Patients enrolled in Phase 1 or Phase 2 of the study may continuetreatment with FPA008 in 28-day cycles for up to 24 weeks or untildisease progression, intolerable toxicity, patient or physician decisionto discontinue, or Sponsor termination of the study. Responding patientswho discontinue treatment while still in response (CR, PR or SD) shouldget follow-up scans at 14 (±2)-week intervals during the Long-TermFollow-up Period to determine the duration of response, unless othertherapy is started for the treatment of PVNS/dt-TGCT or consent iswithdrawn.

All patients should return to the clinic for three End of TreatmentFollow-Up visits irrespective of whether a patient is withdrawn orwithdraws at a planned visit or mid-cycle.

AEs will be assessed from the time the first dose of FPA008 isadministered through 90 days (±7 days) after the last dose of FPA008(see Section 6.2.1.1). All serious adverse events (SAEs) will becollected after signing of the informed consent form through 90 days (±7days) after the last dose (see Section 6.2.1.1).

3.3. Rationale for the Study Design

The Phase 1 component of this study is a dose escalation, open-labelstudy to assess the safety, PK, PD, and preliminary efficacy of FPA008in patients with PVNS/dt-TGCT. The 3+3 dose escalation design isstandard for early stage trials of novel anticancer treatments.

The Phase 2 component is a single-stage trial designed to estimate theobjective response rate with a precision of approximately 20%, assumingthe response rate is similar to that reported for PLX3397 and RG.7155,other potent inhibitors of the CSF1R signaling pathway. The Phase 2component will also allow a more thorough investigation of the safety,PK, and biological effects of FPA008 in the target population for futuretrials.

4. Study Eligibility and Withdrawal Criteria 4.1. Planned Number ofPatients and Study Centers

Phase 1: Approximately 12-15 patients with PVNS/dt-TGCT will beenrolled. Enrollment in Phase 1 will continue until the MTD has beenreached or until the RD for Phase 2 has been defined.

Phase 2: Approximately 30 patients with PVNS/dt-TGCT will be enrolled.The study will be conducted at approximately 12 investigational centersin North America, Europe, and Asia.

4.2. Inclusion Criteria for Study Participation

Patients enrolling into Phase 1 or 2 must meet all of the followinginclusion criteria:

-   1. Understand and sign an Institutional Review Board/Independent    Ethics Committee-approved informed consent form prior to any    study-specific evaluation-   2. Age ≥18 years-   3. Histologically confirmed diagnosis of inoperable PVNS/dt-TGCT or    potentially resectable tumor that would result in unacceptable    functional loss or morbidity as determined by a qualified surgeon or    multi-disciplinary tumor board (must be documented in the CRF during    screening)-   4. Measurable PVNS/dt-TGCT by RECIST 1.1 on MRI-   5. ECOG performance status ≤1-   6. Willing and able to comply with all study procedures-   7. In sexually-active patients (i.e., females of childbearing    potential, who have not undergone menopause as defined by 12    consecutive months of amenorrhea or had a permanent sterilization    procedure and males, who have not had a permanent sterilization    procedure), willingness to use 2 effective methods of contraception,    of which one must be a physical barrier method (condom, diaphragm,    or cervical/vault cap) until 6 months after the last dose of FPA008.    Other effective forms of contraception are permanent sterilization    (hysterectomy and/or bilateral oophorectomy, or bilateral tubal    ligation with surgery, or vasectomy) at least 6 months prior to    Screening. Females <55 years of age should have FSH>40. Female    patients of childbearing potential must be on stable oral    contraceptive therapy or intrauterine or implant device for at least    90 days prior to the study, or abstain from sexual intercourse as a    way of living.

No waivers of these inclusion criteria will be permitted.

4.3. Exclusion Criteria for Study Participation

Patients enrolling into Phase 1 or 2 will be excluded if any of thefollowing criteria apply:

-   1. Prior therapy with an anti-CSF1R antibody-   2. Prior therapy with PLX3397 unless discontinued for intolerance    (i.e., non-progression on prior kinase inhibitor); prior therapy    with imatinib or nilotinib is allowed-   3. CK and liver function tests (including ALT, AST, and total    bilirubin), outside of the range of local laboratory normal at    Screening-   4. Inadequate organ or bone marrow function defined as: hemoglobin    <10 g/dL, absolute neutrophil count <1.5×10⁹/L, platelet count    <100×10⁹/L, serum creatinine >1.5×ULN or calculated creatinine    clearance <30 mL/min-   5. Any surgical procedure of the involved joint within 12 weeks    prior to first study dose administration (except baseline synovium    biopsy, if performed)-   6. Current or history of clinically significant muscle disorders    (e.g., myositis), recent unresolved muscle injury, or any condition    known to elevate serum CK levels-   7. History of congestive heart failure or myocardial infarction <1    year prior to first study dose administration-   8. Decreased cardiac function with NYHA>Class 2-   9. Uncontrolled or significant heart disorder such as unstable    angina-   10. Significant abnormalities on ECG at Screening. QTcF>450 msec for    males or >470 msec for females at Screening-   11. Contraindications to MRI and use of intravenous gadolinium-based    contrast agents-   12. History of severe allergic, anaphylactic, or other infusion    related reaction to a previous biologic agent-   13. Treatment with any anticancer therapy or participation in    another therapeutic clinical study with investigational drugs ≤28    days prior to first dose of FPA008-   14. Known history of ADAs to previous biologic agents-   15. Known history of sensitivity to Tween 20 (polysorbate 20)-   16. Consumption of non-pasteurized milk on a regular basis, or known    significant risk of exposure to opportunistic intracellular    infections such as listeria, or other such pathogens.-   17. Receipt of any vaccine within 28 days prior to first day of    treatment. The effect of FPA008 on mounting an immunologic vaccine    response is not known. Flu or other vaccinations may be administered    while on study but the impact of FPA008 on the safety and efficacy    of the vaccination is unknown.-   18. Current unresolved infection or history of chronic active    clinically significant infection (viral [e.g., HBV, HCV], bacterial,    fungal, or other), which in the opinion of the Investigator would    place the patient at risk from exposure to a CSF1R inhibitor-   19. Known positive test for human immunodeficiency virus (HIV)-   20. Active TB-   21. Positive test for latent TB at Screening (Quantiferon test)-   22. History of prior malignancy, except:    -   Curatively treated non-melanoma skin malignancy    -   Cervical cancer in situ    -   Solid tumor treated curatively more than 2 years previously        without evidence of recurrence-   23. Lack of peripheral venous access or any condition that would    interfere with drug administration or collection of study samples-   24. Any uncontrolled medical condition or psychiatric disorder which    in the opinion of the Investigator would pose a risk to patient    safety or interfere with study participation or interpretation of    individual patient results-   25. Inability to perform and/or comply with study and follow-up    procedures.

No waivers of these exclusion criteria will be permitted.

4.4. Patient Withdrawal and Replacement

The patient has the right to stop treatment or to withdraw from thestudy at any time. Patients may continue to repeat cycles (up to 6cycles) of FPA008 treatment until at least one of the following criteriaapplies:

-   -   Consent withdrawal at the patient's request or at the request of        their legally authorized representative    -   Progression of patient's underlying disease    -   Any event that would pose an unacceptable safety risk to the        patient    -   An intercurrent illness that would affect assessments of the        clinical status to a significant degree and require        discontinuation of therapy    -   A positive pregnancy test at any time during the study    -   At the specific request of the Sponsor or its authorized        representative (for example, if the study is terminated for        reasons of patient safety).

The date and reason for cessation of FPA008 will be documented, and theInvestigator must make every effort to perform the End of TreatmentFollow-Up visits. Patients will be followed for 90 days (±7 days) afterthe last dose of FPA008 for safety; those with ongoing SAEs will befollowed until either resolution or stabilization.

Data from patients who discontinue prematurely will remain part of thestudy database.

4.5. Patient Identification and Enrollment

Patients must be able to provide written informed consent and meet allinclusion criteria and none of the exclusion criteria. No waivers ofinclusion or exclusion criteria will be granted by the Investigator andSponsor or its designee for any patient enrolled in the study. Beforeenrolling a patient, all eligibility criteria must be satisfied.Patients who qualify for Phase 1 of the study will be enrolled into thefirst available cohort. In Phase 2, a cohort of approximately 30patients will be enrolled. A total of approximately 42-45 patients willbe enrolled in the study.

The Investigator may repeat qualifying lab tests and vitals/ECGs priorto enrollment if a non-qualifying finding is considered an error or anacute finding is likely to meet eligibility criteria on repeat testing.

5. Study Drug 5.1. FPA008 Drug Product

The investigational drug product in this study is FPA008. Theinvestigational supply of FPA008 will be provided to the study centersby the Sponsor (or designee) and will be administered to patients in theclinical study by a trained healthcare professional.

A brief description of the FPA008 drug product is provided below:

-   -   Formulation: FPA008 drug substance is comprised of 20 mg/mL        FPA008 in a pH 6.3 buffer containing 20 mM L-histidine, 142 mM        L-arginine, and 0.01% polysorbate 20.    -   How Supplied: FPA008 drug product is supplied for IV        administration as a sterile, aqueous, colorless, pyrogen-free        solution in 5 mL ISO6R Type 1 glass vials fitted with butyl        rubber stoppers and flip-up aluminum seals. Each vial contains a        minimum of 5 mL of a 20 mg/mL solution of FPA008 (approximately        100 mg per vial).    -   Storage Conditions: 2-8° C. (36-46° F.).    -   FPA008 vials and cartons will be labeled according to local        regulations.

5.2. Administration

The dose of FPA008 will be administered based on weight to patients inthis study.

A research pharmacist (or other responsible personnel) will prepare thesolution for administration. After calculating the number of vials,based on the patient's weight, the study drug product will be diluted inapproximately 100 mL of 0.9% sodium chloride solution. Prepared FPA008should be administered hours after preparation (ambient temperature).The IV administration set for FPA008 infusion must contain a 0.22 μmin-line filter or a 0.22 μm syringe filter. FPA008 will be administeredunder medical supervision over approximately 30-minute IV infusion via aperipheral vein or central venous catheter.

If a patient experiences an infusion reaction prior to completion of theinfusion, the infusion must be stopped, and the patient should bepromptly managed according to signs and symptoms, and local clinicalprotocol. The infusion may be restarted at a slower rate if all signsand symptoms have resolved. If the signs and symptoms do not resolve,the infusion should not be restarted. Patient should be kept under closeobservation for at least 1 hour after the end of study drug infusion.

All vials are for single use only. Instructions on study drugpreparation and administration will be provided in a Pharmacy Manual.

5.3. Starting Dose and Dose Modifications

The starting dose level of FPA008 and subsequent dose escalationsbetween cohorts in Phase 1 are described in Section 3.1.2. The dose ofFPA008 in Phase 2 will be determined by evaluation of the data fromPhase 1 of the study.

5.3.1. Dose Escalation of FPA008 Between Cohorts

Dose escalation to the next cohort will only start after the precedingdose cohort has completed the DLT period. Twenty-eight days (DLT period)of safety data must be available for at least 3 safety-evaluablepatients prior to a potential dose-escalation decision by the CRC perthe CRC Charter. In the event that a patient in a cohort is lackingadequate safety data (e.g., due to early withdrawal from study or poorcompliance with the protocol), an additional patient will be enrolled tothe cohort.

Dose escalation in each successive dose cohort will proceed in astepwise fashion. All relevant safety information for the first cohortor the preceding dose cohort will be reviewed by the CRC.

Dose escalation is planned to continue until dose-limiting toxicitiesoccur in 2 or more patients in a cohort. The decision to discontinuedose escalation will be made jointly by the Sponsor and Investigator(s)based on reaching the MTD or a dose level that shows an adequatepharmacodynamic effect.

In Cohort 1, 3 patients will be enrolled initially at a starting dose of1 mg/kg FPA008, given by infusion. The occurrence of DLTs (Section5.3.3) will determine whether the dose will be escalated in subsequentcohorts.

The dose escalation decision rules are summarized in Table 2.

TABLE 2 Decision Criteria for Escalation Number of Patients with DLTsAction  0/3 Open next cohort  1/3 Enroll 3 more in same cohort ≥2/3 Stopenrollment. Enter 3 more patients at dose level below, if only 3 werepreviously entered  1/6 Open next cohort ≥2/6 Stop enrollment. Enter 3more patients at a dose level below or at an intermediate dose level ifthe current dose level is ≥50% higher than the previous dose level.

5.3.1.1. Maximum Tolerated Dose

The selection of the RD will be based on clinical response data as wellas PK and PD profiles. The Sponsor and Investigators may decide todiscontinue dose escalation before reaching the highest planned dose of4 mg/kg or, potentially, evaluate a higher (>4 mg/kg) or intermediate (3mg/kg) dose if the safety, PK, and PD data support evaluation ofdifferent dose levels.

Escalation to an MTD is not intended, however, may occur. If so, the MTDis defined as the highest dose associated with DLTs in Cycle 1 in lessthan 33% of patients receiving FPA008 administered on Day 1 and Day 15of a planned 28-day cycle.

If the MTD is not reached during Phase 1 or subsequent cycles oftreatment in Phase 1 provide additional insight regarding the safetyprofile, the RD may be selected depending on overall tolerability, PK,and estimates of efficacious exposures extrapolated from ongoingclinical evaluations.

5.3.1.2. Toxicity at Lowest Dose Level

If the first dose level of 1 mg/kg is, unexpectedly, found to exceed anMTD, then decisions on how to proceed will be based on safety,tolerability, and PK data; and will be agreed on between theInvestigators and the Sponsor.

A lower dose level may be chosen as the next cohort.

5.3.2. Dose Escalation within a Cohort

Intra-patient dose escalation above the starting dose is not permitted.If a patient's dose is decreased for an AE, dose escalation to theoriginally assigned dose may occur after resolution of the AE and afterdiscussion with and approval by the Sponsor. Recurrence of the AE togreater than Grade 2 will result in permanent dose reduction withoutre-escalation.

5.3.3. Dose-Limiting Toxicity

DLTs are defined as any of the following events that occur during Cycle1 of treatment and are assessed by the Investigator with concurrence bythe CRC as related to FPA008. As applicable, events will be classifiedaccording to the NCI CTCAE (Version 4.03).

Any Grade ≥3 related event except the following:

-   -   For elevations in ALT, AST, or CK without associated clinical or        laboratory abnormality, the following DLT definitions apply:        -   CK associated DLT: CK>10× the upper limit of normal (ULN)        -   ALT or AST associated DLT:            -   ALT or AST>8×ULN            -   ALT or AST>3×ULN and associated total bilirubin >2×ULN

Phase 1 patients who experience a DLT during the DLT assessment period(Cycle 1) will be removed from study treatment. Patients experiencingtoxicity in cycles after Cycle 1 that would be considered dose limitingduring the DLT assessment period are not required to discontinue studyparticipation in the study.

5.3.4. Dose Modification Criteria

Dose reductions may be permitted for patients on prolonged treatmentbeyond the DLT period in Phase 1 or any patient in Phase 2 per thefollowing guidelines. If dose reductions or interruptions that do notfall within these guidelines are being considered by the Investigator,these will require discussion with and approval by the Sponsor.

Patients may miss up to 2 consecutive doses (up to 6 weeks betweendoses) for adverse or other events and may resume the study drug if theevent returns to baseline or ≤Grade 1 within 6 weeks of treatmentinterruption. Omission of additional dosing longer than 6 weeks foradverse events will necessitate the patient's discontinuation from thestudy unless allowed by the Sponsor. Patients may miss doses in thecourse of participation in the study, including missed doses forscheduled vacations or other personal reasons as needed, but not morethan 2 doses sequentially.

The Cycle 2, Day 1 infusion of FPA008 can only be administered aftercompletion of the 28-day DLT window. All subsequent infusions can beadministered with a ±3 day window. Patients should not have 2 doses ofFPA008 within 7 days. The first dose of each cycle is considered Day 1of each cycle, cycles will repeat every 28 days unless there is atreatment delay. Patients can have treatment delay of Day 1 of thesubsequent cycle as long as the Day 1 treatment is within 6 weeks of thelast treatment.

If a patient has an elevation of CK>5×ULN but <10×ULN, the nextscheduled study treatment may be delayed up to a maximum of 28 days fromthe last administered treatment dose, based on Investigator assessmentof accompanying signs, symptoms, and additional laboratory findings(Table 3).

In the event of ALT or AST elevations:

-   -   At any time, if the elevation in ALT or AST is >3×ULN and        accompanied by an elevation in total bilirubin of >2×ULN, FPA008        should be held, and the patient should be withdrawn into safety        follow-up.    -   If ALT or AST is elevated >3×ULN but <5×ULN without        bilirubin >2×ULN, the test should be repeated at the next        scheduled visit and if ALT or AST are persistently high but        still <5×ULN, the dose can be delayed up to a maximum of 28        days. The minimum interval between 2 consecutive doses cannot be        less than 7 days.    -   If a patient has an elevation of ALT or AST>5×ULN but <8×ULN,        the next scheduled study treatment may be delayed up to a        maximum of 28 days from the last administered treatment dose,        based on Investigator assessment of accompanying signs,        symptoms, and additional laboratory findings.    -   If a patient experiences a Grade 3 or higher ALT or AST adverse        event attributed to study treatment, or ALT or AST        elevation >8×ULN regardless of attribution, the study drug        should be discontinued and the patient should be withdrawn from        study treatment. Withdrawal from treatment should also occur for        patients with ALT or AST elevations >3×ULN accompanied by an        elevation in total bilirubin of >2×ULN.

In the event of CK elevations:

Treatment should be discontinued for a CK elevation >10×ULN

TABLE 3 Dose Delay and Modification Guidelines for Study Drug-RelatedEvents other than ALT, AST and CK Toxicity Grade FPA008 Dose DoseSchedule 1 Continue 100% of dose No delay or missed dose required 2Continue 100% of dose No delay or missed dose required 3 Phase 1: Maycontinue at next lower dose level Up to 2 missed doses allowed evaluated(e.g., if a Grade 3 AE occurs at 2 without Sponsor approval to mg/kg,patient may continue at 1 mg/kg) continue following recovery to baselineor Grade 1; If at lowest dose level evaluated (i.e., 1 mg/kg), use Phase2 dose modification guideline Phase 2: Continue 75% of starting dosefollowing recovery to baseline or Grade 1 4 Phase 1: May continue atnext lower dose level Up to 2 missed doses allowed evaluated (e.g., if aGrade 3 AE occurs at without Sponsor approval to 2 mg/kg, patient maycontinue at 1 mg/kg) continue following recovery to baseline or Grade 1;If at lowest dose level evaluated use Phase 2 Phase 2: Continue 50-75%of starting dose following recovery to baseline or Grade 1Note: Table 3 applies to adverse events other than the ALT, AST, and CKrules above.

If a patient's dose is decreased for an adverse event, dose escalationto the originally assigned dose may occur after resolution of the AE andafter discussion with and approval by the Sponsor. Recurrence of the AEto greater than Grade 2 will result in permanent dose reduction withoutre-escalation.

5.3.5. Dose Interruptions During Study Drug Infusion

Infusion of FPA008 must be stopped if any AE≥Grade 3 occurs during theinfusion. If bronchospasm or dyspnea occurs in a patient duringinfusion, the infusion should be stopped.

In addition, at the Investigator's discretion, the infusion rate may bereduced or stopped if a less severe AE (Grade 1 or 2) occurs during theinfusion. If a Grade 3 or less severe AE resolves within 6 hours, theinfusion may be restarted at half the previous rate. If the same AEappears again with the same severity at any time during the restartedinfusion, the infusion should be discontinued, and no further dosing ofstudy drug will occur without consultation with the Sponsor (ordesignee).

If a patient experiences an infusion reaction, the patient's vital signs(temperature, blood pressure, pulse, and respiration rate) should bemonitored during the infusion, as well as every 30 minutes after theinfusion for a minimum of 1 hour and until resolution of the infusionreaction.

Systemic hypersensitivity reactions should be managed under the directsupervision of a physician and according to treatment protocols ineffect at the investigational site. However, in the absence of such aprotocol, the standardized treatment protocol provided in Appendix 6should be used.

5.4. Blinding and Breaking the Blind

Blinding and breaking the blind are not applicable as this is anopen-label study.

5.5. Drug Accountability

The Investigator or appropriately qualified staff is responsible formaintaining accurate study drug accountability records throughout thestudy.

The Investigator is responsible for returning all unused study drug tothe Sponsor (or designee), and must verify that no remaining suppliesare in the Investigator's possession. The study site is permitted todestroy used or partially used study drug vials according to the sitepolicy once Sponsor (or designee) approval of its documented destructionprocedure has been obtained. Accurate records of all study drug receivedat, dispensed from, returned to, and disposed of by the study siteshould be reconciled and recorded by using a drug inventory log duringand on completion of the study.

5.6. Investigational Product Compliance

Only qualified trained site personnel may administer FPA008. Pharmacypersonnel trained in the study requirements will monitor compliance withthe treatment assignments. FPA008 will be infused over approximately 30minutes via a peripheral vein or central venous catheter by a trainedhealthcare professional. Records of study medication administered (date,start and stop time, and dose administered relative to time ofpreparation) will be recorded on the patient's electronic case reportform (eCRF).

5.7. Concomitant Medication and Treatment

All concomitant medications including herbal and other non-traditionalremedies are to be captured on the eCRF. The following parameters willbe collected: generic name, route of administration, start date, stopdate, dosage, frequency, and indication. Any changes in the dosage orregimen of a concomitant medication also must be recorded on the eCRF.

At Screening, patients will be asked what medications they have takenduring the previous 28 days. At each subsequent study visit, patientswill be asked about any changes in concomitant medications since theprevious visit.

Throughout the study, Investigators may prescribe any concomitantmedications or treatments deemed necessary to provide adequatesupportive care except for the following:

Other experimental drugs or devices

Other systemic medication for treatment of PVNS such as imatinib ornilotinib

Chronic daily corticosteroids ≥10 mg/kg prednisone (or equivalent)

If a patient uses a prohibited medication or undergoes tumor resection,the Sponsor should be consulted for a decision on whether the patientshould be withdrawn from the study.

Patients may initiate or continue pain medications as dictated bystandard clinical practice. Transfusions are permitted as needed.

No routine premedication will be administered for the initial FPA008dose. If a patient develops nausea, vomiting, or other infusion-relatedAEs, the patient may be pre-medicated with antiemetics, steroids, orantihistamines prior to subsequent infusions of FPA008 at the discretionof the Investigator. The treatment will be administered according to theinstitution's standard practice, and should be captured on the patient'seCRF.

6. Parameters and Methods of Assessment

Safety of FPA008 will be assessed by monitoring AEs and changes inphysical examinations (including weight), vital signs, 12-lead ECGs,disease related signs and symptoms, and clinical laboratorymeasurements. Blood samples will be evaluated for immunogenicity.

6.1. Tumor Response Parameters

MRI will be performed at Screening (within 28 days prior to first dose),4, 8, and 16 weeks following the start of treatment (Appendix 1). MRIsshould be completed within 1 week of dose administration when re-imagingis scheduled. All patients should have tumor response parametersassessed at the 30 days (±7 days) and 90 days (±7 days) End of TreatmentFollow-up Visits, unless a tumor assessment has been performed withinthe previous 6 weeks or if tumor progression was previously determined.

Clinical assessment of health outcomes (function, symptoms) will be doneat Screening, C1D15 (pre-dose), C2D1 (pre-dose), and then on Day 1(pre-dose) for all subsequent cycles through 24 weeks or until treatmentis discontinued.

Patients who have not progressed after the End of Treatment Follow-upPeriod are to be followed every 14 weeks (±2 weeks) (see section 7.2.10)until progression, the patient undergoes local therapy (e.g., resection,radiation) or a new systemic therapy is initiated, for up to 52 weeksfollowing C1D1.

Response will be evaluated using RECIST 1.1 (Eisenhauer, 2009) and theTotal Volume Score (Tap, 2014) for radiologically measurable disease.MRI will be used for radiologic measurement of tumor.

Linear measurements of diffuse PVNS are complicated by a number offactors. Since the tumors are characteristically amorphous and canfluctuate in shape, correlation of serial linear measurements withchanges in tumor volume depends on where the measurements are made.However, poor contrast between the tumor and adjacent tissue in certainlocations limits where these measurements can be made accurately.Additionally, linear measurements are highly vulnerable to variations inthe plane of section on serially acquired images. Nevertheless, giventhe longstanding tradition of RECIST in oncology clinical trials, linearmeasurements of up to two measurable tumor locations per joint or tendonsheath, as per RECIST 1.1 guidelines, will be used in this study as areference.

Radiologic response will also be assessed by the TVS. The TVS has beenused in a recent study of PVNS that showed a treatment effect of a CSF1Rtyrosine kinase inhibitor.

The clinical impact of PVNS is believed to stem primarily from the masseffect and local structural damage caused by tumor growth within limitedarticular and peri-articular spaces. Tumor growth interferes with jointflexion and can also destroy the structural and functional integrity ofjoints as tumor invades local bones and soft tissues. The goals ofimaging in clinical trials of PVNS are thus to monitor changes in thevolume of the tumor and to monitor any associated damage to localtissues.

Volumetric quantification of diffuse PVNS is complicated by irregularshape of the tumor, heterogeneous contrast between the tumor and itssurrounding structures, and variable enhancement by intravenousgadolinium-based contrast agents. Tumor margins are thus difficult todelineate in certain locations, making automated segmentation unreliableand manual segmentation subjective. Hemosiderin deposition usually doesnot improve contrast substantially, as the distribution of hemosiderinis variable, heterogeneous, and not always confined to the tumor.Additionally, discriminating viable tumor from inactive scar tissue orintra- and peri-lesional fluid collections can be difficult. Under suchcircumstances, visual scoring using semi-quantitative ordinal scales isusually more reliable than volumetric quantification, as has been theexperience with synovial thickening assessments in clinical trials ofarthritis. Trials employing MRI for evaluation of anti-inflammatorytherapy for arthritis have been based on semi-quantitative scoring.

The TVS scale is based on 10% increments of the estimated volume of themaximally distended synovial cavity, which varies from joint to joint,or of the maximally distended tendon sheath (assumed to be three timesthe diameter of the involved tendon). Thus, a tumor that is equal to thevolume of a maximally distended synovial cavity or tendon sheath wouldbe scored 10, whereas a tumor that was 70% of that volume would bescored 7, and a tumor twice that volume would be scored 20.

Individual patient outcomes by TVS are classified according to thefollowing criteria:

-   -   Complete Response (CR): lesion completely gone    -   Partial Response (PR): ≥50% decrease in volume score relative to        baseline    -   Progressive Disease (PD): ≥30% increase in volume relative to        lowest score during the study whether at baseline or some other        visit    -   Stable Disease (SD): does not meet any of the prior criteria        based on score during study.    -   Note: Tumor assessments performed as part of the patient's        standard of care within 28 days (4 weeks) of the first dose of        FPA008 do not need to be repeated during Screening.

6.2. Safety Parameters 6.2.1. Laboratory Parameters

Laboratory assessments will be performed locally at each study site'slaboratory by means of their established methods. Before starting thestudy, the Investigator will provide the Sponsor (and/or designee) witha list of the normal ranges and units of measurement.

Blood samples should be taken using standard venipuncture techniques.The following laboratory parameters (Table 5) will be determined inaccordance with the Schedule of Assessments (Appendix 1):

TABLE 5 Laboratory Assessments Hematology: Complete blood cell (CBC)with differential: white blood cells (WBC) platelets ANC hemoglobinneutrophils (%) hematocrit eosinophils (%) red blood cells (RBC)basophils (%) RBC indices: lymphocytes (%) mean corpuscular volume (MCV)monocytes (%) mean corpuscular hemoglobin (MCH) mean corpuscularhemoglobin concentration (MCHC) Urinalysis: Dipstick (appearance, color,pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite,urobilinogen, and occult blood) If dipstick is positive (2+ or greater)for blood or protein, perform a microscopic examination. Clinicalchemistry: albumin alkaline phosphatase glucose ALT (SGPT) lactatedehydrogenase (LDH) AST (SGOT) Troponins (cardiac and skeletal) CKisoenzymes (if CK abnormal) blood urea nitrogen (BUN) potassium calciumsodium chloride total bilirubin carbon dioxide (CO2) total cholesterolcreatinine total protein direct bilirubin uric acid phosphate CK(creatinine kinase) Other chemistry tests: Magnesium Coagulation: INRAPTT PT Serum pregnancy test: For females of childbearing potentialonly. Other test: Antinuclear antibodies (ANA)

Abnormal laboratory results that lead to a change in patient treatmentmanagement (e.g., dose delay, requirement for additional medication ormonitoring) are considered clinically significant for the purposes ofthis study and will be recorded on the AE page of the eCRF. Valuesmeeting SAE criteria must be reported as SAEs.

The Investigator's determination of relationship of the AE to drugtherapy and counter measures undertaken will be documented and noted onthe eCRF.

6.2.2. Vital Signs

Vital signs will include sitting blood pressure, pulse, respirationrate, and temperature. All vital signs will be obtained after thepatient has been resting for at least 5 minutes. Vital signs will beperformed in accordance with the Schedule of Assessments (Appendix 1).

6.2.3. Electrocardiograms

Twelve-lead ECGs will be performed in accordance with the Schedule ofAssessments (Appendix 1). The Investigator must review the ECG, documentthis review in the source documents, and record any clinicallysignificant changes that occur during the study as an AE in the eCRF.

6.2.4. Pregnancy

Pregnancy is an exclusion criterion and women of childbearing potentialmust not be considering getting pregnant during the study. A negativeserum pregnancy test fewer than 5 days prior to first dosing with FPA008treatment is mandatory. Patients of reproductive potential (males andfemales) must practice 2 effective contraception methods (Section 4.2).during the study and for 6 months after last treatment.

6.2.5. Physical Examinations

Physical examinations will be performed in accordance with the Scheduleof Assessments (Appendix 1).

A complete physical examination including height and weight will beperformed at Screening. Complete physical examinations should beconducted per the Schedule of Events (Appendix 1).

6.2.6. Immunogenicity

Immunogenicity, defined as an immune response to FPA008, will beassessed by measurement of total anti-FPA008 antibodies from allpatients. Immunogenicity testing will consist of screening,confirmation, and titration.

Samples for immunogenicity assessment will be drawn from each patient atthe time points designated in Appendix 2. Samples for immunogenicitytesting will be collected and processed according to the instructionprovided in the Laboratory Manual.

6.2.7. ECOG Performance Status

ECOG performance status will be assessed at Screening, within 72 hoursprior to dosing, and through the End of Treatment Follow-up Period(Appendix 1).

6.3. Pharmacokinetic Parameters

In this study, samples for the determination of serum FPA008 will becollected as outlined in Appendix 2. The sampling will allowdetermination of the exposure (AUC), C_(max), C_(min) (troughconcentration), CL, and V_(ss). Other PK parameters, such asaccumulation ratio and half-life, may also be calculated as data allow.

These samples will be collected and processed according to theinstructions provided in a separate Laboratory Manual.

6.4. Pharmacodynamic Parameters

The following exploratory endpoints will be assessed (Appendix 2):

-   -   Serum: CSF1 and IL34 ligand concentration, CTx, and TRAP5b bone        resorption marker concentrations    -   Whole blood—CD14⁺/CD16⁺ monocyte subsets levels

The following procedures (see Appendix 1) only apply to patients whosign the applicable Optional Research Informed Consent Form; the purposeof these procedures is to understand the impact of FPA008 on changes inlocal biomarkers of inflammation (synovium and synovial fluid) anddistribution of FPA008 to the involved joint (synovial fluid):

-   -   Synovium (optional)    -   Evaluate synovial biopsy for CSF1 gene translocation (if not        previously done) at pretreatment    -   Baseline and on treatment synovial biopsy, IHC for:    -   CSF1 and CSF1R    -   CD68    -   Synovial fluid (optional)    -   FPA008 concentration; cellular component for above markers by        IHC.

6.5. Patient and Clinician Reported Outcome Measures

Clinical assessment of health outcomes (function, symptoms) will be doneat Screening, C1D15 (pre-dose), C2D1 (pre-dose), and then on Day 1(pre-dose) for all subsequent cycles through 24 weeks or until treatmentis discontinued, and through the End of Treatment Follow-up Period.Patients who have not progressed and enter Long-Term Follow-up are to befollowed every 14 weeks (±2 weeks) until progression, the patientundergoes local therapy (e.g., resection, radiation) or a new systemictherapy is initiated, for up to 52 weeks following C1D1. The followingtools will be used to collect exploratory endpoint data on symptom andfunctional outcomes:

-   -   Ogilvie-Harris (OH) Scale (Appendix 4): This tool was developed        specifically for patients with PVNS (Ogilvie-Harris, 1992) and        has been used in other PVNS publications (De Ponti, 2003; Rhee,        2010). Characteristics of this tool include the following:    -   It is a clinician reported outcome (CRO) measure    -   It is based on a 0-3 interval scale for each of the 4 domains:    -   Pain    -   Synovitis/effusion    -   Range of motion    -   Functional capacity    -   It uses lower end of the scale (score min=0) indicating severe        disability, pain and functional loss and the higher values        (score max=12) indicating no disability. Scores can be summed        and classified as follows:    -   Poor condition (0-3 points)    -   Fair condition (4-6 points)    -   Good condition (7-9 points)    -   Excellent condition (10-12 points)    -   Is selected for this study relative to other location-specific        outcome measures (such as the WOMAC, KOOS, etc.) because:    -   It can be used in any joint affected by PVNS    -   It is specific to the disease of PVNS by addressing the        symptomology of PVNS (pain and synovitis/effusion)    -   It has a low respondent burden—4 “questions”    -   Has, however, only been published in patients with PVNS of the        knee and has not been validated against a gold-standard outcomes        measure such as the SF-36 or EQ-5D-5L scales. Thus the EQ-5D-5L        scale (a patient-reported outcome) will also be used in this        study.    -   EQ-5D-5L (Appendix 5): This is a well-known generic measure of        health status originally published in 2001 (Rabin) which        includes the following characteristics:    -   Has been used in numerous diseases and chronic conditions in        multiple countries    -   Is a patient reported outcome (PRO) measure    -   Is used as a functional assessment in an active PVNS clinical        trial (MCS110, Novartis)    -   Is based on a 0-5 interval scale for each of the 5 domains with        the lower end of the scale (score min=0) anchored at death (or        worse than death) health state and the higher values (score        max=100) anchored at perfect health state:    -   (1) Mobility    -   (2) Self-care    -   (3) Usual activities    -   (4) Pain/discomfort    -   (5) Anxiety/depression    -   It also uses a VAS to measure the responders current health on a        20-cm vertical line with 0=“worst imaginable health” and        100=“best imaginable health”    -   It has been validated in multiple countries and is available in        119 languages. It has a low respondent burden with only 6        questions and is available in several media (paper, web, and        tablet).

7. Study Conduct 7.1. Overview of Patient Assessments

After an initial Screening period of up to 28 days (4 weeks), patientswill be treated with FPA008 every 2 weeks (±3 days) in 28-day cycles,and FPA008 will be administered over approximately 30 minutes. All timepoints of assessments should be completed in the timeframe stated.Assessments performed prior to the patient signing the informed consentare acceptable only if confirmed to have been standard of care.

The schedule of detailed patient assessments is shown in Appendix 1 andAppendix 2. Instructions for the sampling and processing of PK, PD, andimmunogenicity data are described in a separate, protocol-specificlaboratory manual.

7.2. Study Assessments and Procedures by Visit 7.2.1. Screening Period(Day −28 to Day 0)

Patients who have fully consented to participation in the study willundergo Screening assessments within 28 days (4 weeks) prior toadministration of the first infusion of FPA008 (unless otherwisestated). To determine if the patient meets all the inclusion criteriaand does not violate the exclusion criteria, the following procedureswill be performed (Appendix 1):

-   -   Written, signed informed consent must be collected prior to any        study-specific procedures    -   Complete medical and disease history    -   Demographic and baseline characteristics    -   Vital signs (sitting blood pressure, pulse, respiration rate,        and temperature [° C.] after 5 minutes rest)    -   Complete physical examination, including height and weight    -   ECOG performance status evaluation    -   12-lead ECG (required at Screening, and if clinically indicated        during the study)    -   AE reporting, if applicable    -   Document prior and concurrent medications    -   Quantiferon test (for latent TB)    -   Clinical safety labs as outlined in Table 5 (including ANA)    -   Ogilvie-Harris and EQ-5D-5L assessments    -   Optional archival tissue    -   Optional synovial biopsy    -   Optional synovial fluid aspirate    -   Serum pregnancy test (beta-human chorionic gonadotropin        [β-HCG]), ≤5 days prior to Cycle 1, Day 1, for women of        childbearing potential    -   Radiological imaging: MRI of the involved joint(s) is to be        performed within 28 days prior to the first infusion of FPA008.        If the MRI is performed as part of the patient's standard of        care within 28 days of the first study infusion it does not need        to be repeated if the documentation of results is provided and        is adequate for an assessment.

Note: A protocol-specific patient registration form must be submitted tothe Sponsor (or designee) to confirm patient eligibility prior toinitiation of study treatment.

7.2.2. Treatment Allocation (Dosing Assignment)

This is an open-label study. Enrollment numbers will be faxed or emailedto the Investigator (or designee). The Sponsor (or designee) willmaintain records of the number of patients treated within a specificcohort and will determine to which treatment cohort newly enrolledpatients will be assigned.

7.2.3. Phases 1 and 2: Cycle 1, Day 1

The following procedures will be performed:

-   -   Prior to FPA008 infusion (within 72 hours unless otherwise        stated):    -   Verification of eligibility    -   Update medical and disease history to capture any changes from        Screening    -   AE reporting, if applicable    -   Review of concomitant medications    -   Record weight    -   Vital signs (sitting blood pressure, pulse, respiration rate,        and temperature [° C.] after 5 minutes rest)    -   ECOG performance status evaluation    -   Clinical safety labs with the exception of urinalysis and ANA as        outlined in Table 5    -   Serum β-hCG (evaluated by local laboratories) will be performed        ≤5 days prior to the first dose of FPA008 only on women of        childbearing potential    -   PK, ADA, serum biomarkers and CD14⁺/CD16⁺ monocytes sample        collections (within ≤4 hours) as outlined in Appendix 2.    -   Study drug administration: Administer FPA008, by IV infusion        over approximately 30 minutes    -   Post FPA008 administration:    -   PK, serum biomarkers and CD14⁺/CD16⁺ monocytes sample        collections (±5 min) as outlined in Appendix 2.    -   Post-dose Vital signs (sitting heart rate, blood pressure,        respiration rate, and temperature [° C.] after 5 minutes rest)        at the following time points after completion of the IV        infusion:    -   5 minutes, 15 minutes, 30 minutes, and 1 hour    -   AE reporting, if applicable    -   Review of concomitant medications

7.2.4. Phases 1 and 2: Cycle 1, Day 2

PK, serum biomarkers, and CD14⁺/CD16⁺ monocytes sample collections asoutlined in Appendix 2.

AE reporting, if applicable

Review of concomitant medications

7.2.5. Phases 1 and 2: Cycle 1, Day 8

Study patients will return to the study center on Day 8 (±2 days). Notreatment will be administered.

The following assessments will be completed:

-   -   Vital signs (sitting blood pressure, pulse, respiration rate,        and temperature [° C.] after 5 minutes rest)    -   Clinical safety labs with the exception of ANA, as outlined in        Table 5    -   PK, serum biomarkers, CD14⁺/CD16⁺ monocytes sample collections        as outlined in Appendix 2.    -   AE reporting, if applicable    -   Review of concomitant medications

7.2.6. Phases 1 and 2: Cycle 1, Day 15

Study patients will return to the study center on Day 15, and thefollowing assessments will be completed.

-   -   Prior to FPA008 infusion (within ≤72 hours unless otherwise        stated):        -   Record weight        -   Vital signs (sitting blood pressure, heart rate, respiration            rate, and temperature [° C.] after 5 minutes rest)        -   Clinical safety labs with exception of urinalysis and ANA as            outlined in Table 5        -   Ogilvie-Harris and EQ-5D-5L assessments        -   PK, ADA, serum biomarkers and CD14⁺/CD16⁺ monocytes sample            collections (within ≤4 hours) as outlined in Appendix 2        -   Update medical and disease history        -   AE reporting, if applicable        -   Review of concomitant medications    -   Study drug administration: Administer FPA008, by IV infusion        over 30 minutes    -   Post FPA008 administration:        -   PK sample collection 15 minutes (±5 min) after end of            infusion (as outlined in Appendix 2)        -   Post-dose Vital signs (sitting heart rate, blood pressure,            respiration rate, and temperature [° C.] after 5 minutes            rest) at the following time points after completion of the            IV infusion:            -   5 minutes, 15 minutes, 30 minutes, and 1 hour        -   12-lead ECG (within approximately 30 minutes post-dose after            PK/PD sample collection)        -   AE reporting, if applicable        -   Review of concomitant medications

7.2.7. Phase 1: End of Cycle 1

For Phase 1 patients, if at the end of Cycle 1 the Investigatordetermines that the patient may benefit from continued dosing withFPA008, entry into the Extended Treatment Period may be offered.

If the patient is continuing onto the Extended Treatment Period (Cycle 2and beyond), proceed to procedures outlined in Section 7.2.8.

If the patient does not qualify to receive further doses of FPA008, thepatient will return to the clinic for the End of Treatment Follow-upVisits.

7.2.8. Phase 1 Extended Treatment/Phase 2 Cycle 2 and Subsequent Cycles

Phase 1 Extended treatment may begin on Cycle 2, Day 1. Dosing will bediscontinued if the patient experiences either disease progression orunacceptable toxicity.

At each infusion visit, patients are to remain at the study site aftereach administration of FPA008 until completion of all post-doseassessments for safety monitoring. The following assessments will beperformed at each visit unless otherwise noted ((Appendix 1):

7.2.8.1. Phases 1 and 2: Cycle 2 and Subsequent Cycles, Day 1

Prior to each infusion of study drug (within ≤72 hours unless otherwisestated):

-   -   Vital signs (sitting heart rate, blood pressure, respiration        rate, and temperature [° C.] after 5 minutes rest)    -   Complete physical examination including weight at Cycle 2, 4,        and 6    -   ECOG performance status evaluation    -   Ogilvie-Harris and EQ-5D-5L assessments    -   Clinical safety labs with the exception of urinalysis and ANA as        outlined in Table 5    -   PK, ADA, serum biomarkers and CD14⁺/CD16⁺ monocytes sample        collections (within ≤4 hours) on Day 1 of Cycles 2, 3, and 5, as        outlined in Appendix 2    -   MRI of the involved joint(s) using the same physical or        radiologic parameter(s) used to evaluate baseline tumor        measurements are to be done within 1 week of C2D1, C3D1, and        C5D1    -   Optional synovial biopsy up to −2 days prior to dose        administration (Cycle 2 only) as outlined in Appendix 1    -   Optional synovial fluid aspirate up to −2 days prior to dose        administration (Cycle 2 only) as outlined in Appendix 1    -   AE reporting, if applicable    -   Review of concomitant medications

Study drug administration: Administer FPA008, by IV infusion overapproximately 30 minutes

Post study drug administration:

-   -   Post-dose Vital signs (sitting heart rate, blood pressure,        respiration rate, and temperature [° C.] after 5 minutes rest)        at the following time points after completion of the IV        infusion:    -   5 minutes, 15 minutes, 30 minutes, and 1 hour    -   PK sample collection 15 minutes (±5 min) after end of infusion        on Day 1 of Cycles 3, and 5 (Appendix 1).    -   AE reporting, if applicable    -   Review of concomitant medication

7.2.8.2. Phases 1 and 2: Cycle 2 and Subsequent Cycles, Day 15

Prior to each infusion of study drug (within ≤72 hours unless otherwisestated):

-   -   Vital signs (sitting heart rate, blood pressure, respiration        rate, and temperature [° C.] after 5 minutes rest)    -   Clinical safety labs with the exception of urinalysis and ANA as        outlined in Table 5    -   AE reporting, if applicable    -   Review of concomitant medications

Study drug administration:

-   -   Administer FPA008, by IV infusion over approximately 30 minutes

Post study drug administration:

-   -   Post-dose Vital signs (sitting heart rate, blood pressure,        respiration rate, and temperature [° C.] after 5 minutes rest)        at the following time points after completion of the IV        infusion:        -   5 minutes, 15 minutes, 30 minutes, and 1 hour    -   12-lead ECG (within approximately 30 minutes post-dose after        PK/PD sample collection)    -   AE reporting, if applicable    -   Review of concomitant medication

7.2.9. End of Treatment Follow-Up Period

Patients will return to the study center three times, approximately 30days (±7 days), 60 days (±7 days), and 90 days (±7 days) after theirlast infusion of FPA008, to complete the End of Treatment Follow-upPeriod.

The following assessments will be performed:

-   -   Vital signs (sitting pulse, blood pressure, respiration rate,        and temperature [° C.] after 5 minutes rest)    -   12-lead ECG at the 30 days (±7 days) End of Treatment Follow-up        Visit only    -   Complete physical examination at the 30 days (±7 days) End of        Treatment Follow-up Visit only. Weight is to be recorded at all        visits    -   ECOG performance status evaluation    -   Clinical safety labs as outlined in Table 5 (including ANA at        the 30 days (±7 days) End of Treatment Follow-up Visit only)    -   PK, ADA, serum biomarkers and CD14⁺/CD16⁺ monocytes sample        collections as outlined in Appendix 2    -   Serum β-hCG (evaluated by local laboratories) in women of        child-bearing potential    -   MRI of the involved joint(s), Ogilvie-Harris, and EQ-5D-5L        assessments at the 30 days (±7 days) and 90 days (±7 days) End        of Treatment Follow-up Visits. These can be omitted if performed        within 6 weeks prior or if tumor progression was previously        determined.) Patients who have not progressed at treatment        discontinuation and agree to continue participation in the study        are to be followed every 14 (±2) weeks until progression, the        patient undergoes local therapy (e.g., resection, radiation) or        a new systemic therapy is initiated, for up to 52 weeks        following C1D1.    -   AE reporting, if applicable    -   Review of concomitant medications

7.2.10. Long-Term Follow Up Period

Patients who have not progressed should continue onto Long-TermFollow-up after completing the End-of-Treatment Follow-up Period.Patients will be followed every 14 weeks (±2 weeks) until progression,the patient undergoes local therapy (e.g., resection, radiation) or anew systemic therapy is initiated, for up to 52 weeks following C1D1.

The following assessments will be performed:

-   -   Clinical safety labs with the exception of urinalysis and ANA    -   PK, ADA, serum biomarkers and CD14⁺/CD16⁺ monocytes sample        collections as outlined in Appendix 2    -   MRI of the involved joint(s), Ogilvie-Harris, and EQ-5D-5L        assessments    -   AE reporting for ongoing adverse events thought to be related to        study treatment, if applicable    -   Reporting of concomitant medications (local therapy (e.g.,        resection, radiation) or a new systemic therapy only)

8. Statistical Methods

Before database lock, a separate statistical analysis plan (SAP) will befinalized, providing detailed methods for the analyses outlined below.

Any deviations from the planned analyses will be described and justifiedin the final integrated study report.

8.1. Study Patients 8.1.1. Disposition of Patients

The number and percentage of patients evaluable for DLT, safety,efficacy, PK and PD will be presented. Reasons for withdrawal will alsobe summarized.

8.1.2. Protocol Deviations

A summary of the number and percentage of patients with protocoldeviations by type of deviation will be provided. Deviations will bedefined in the SAP prior to database lock.

8.1.3. Analysis Populations

The following analysis populations are defined for the study:

-   -   Safety Population—all patients who have received any portion of        at least one dose of FPA008.    -   DLT-Evaluable Population—all patients enrolled into Phase 1 of        the study who received at least 2 doses of FPA008 and completed        Cycle 1 of treatment, or who experienced a DLT in Cycle 1.    -   PK-Evaluable Population—all patients who have received at least        one dose of FPA008 and have had adequate PK assessments drawn        for determination of the PK profile.    -   Efficacy-Evaluable Population—all patients who met eligibility        criteria, received at least 1 dose of FPA008, have measurable        tumor lesions at baseline, and have at least 1 post-baseline        disease assessment.    -   Intent-to-Treat Population (ITT)—all enrolled patients. Patient        without post-baseline disease assessment will be considered as        non-responder.

8.2. General Considerations

All analyses will be descriptive and will be presented by dose group andoverall as appropriate. Patient data from Phase 2 will be summarized asa separate group. All patients dosed at the RD will also be summarized.Data collected in this study will be presented using summary tables andpatient data listings. Continuous variables will be summarized usingdescriptive statistics, specifically the number of valid cases,arithmetic mean, median, standard deviation (SD), minimum, and maximum.Categorical variables will be summarized by frequencies and percentages.

A change to the data analysis methods described in the protocol willrequire a protocol amendment only if it alters a principal feature ofthe protocol. The SAP will be finalized prior to database lock. Anychanges to the methods described in the final SAP will be described andjustified in the clinical study report.

8.3. Demographics, Baseline Characteristics, and Concomitant Medications

Demographic data, medical history, other baseline characteristics,concomitant disease, and concomitant medication will be summarized bycohort and overall. To determine whether the criteria for study conductare met, corresponding tables and listings will be provided. These willinclude an assessment of protocol deviations, study drug accountability,and other data that may impact the general conduct of the study.

8.4. Treatment Compliance

Treatment administration will be summarized by cohort including doseadministration, dose modifications or delays, cumulative dose, averagedose, number of infusions, and the duration of therapy.

8.5. Analyses of Tumor Response

Patients will be classified according to their best overall tumorresponse (complete response [CR], partial response [PR], stable disease[SD], or progressive disease [PD]). Frequencies, proportions, and exact95% CI of patients, when appropriate, stratified by their best overalltumor response will be calculated. Patients with a best overall tumorresponse of CR or PR with duration of at least 4 weeks (28 days) will befurther classified as having an objective tumor response. Listing ofpatients with an objective tumor response will be presented.

Patients will be classified for response by RECIST 1.1 and the TotalVolume Score. The Tumor Volume Score classifies response according tothe following definitions: Complete Response [(CR) lesion completelygone by the end of the study], Partial Response [(PR)≥50% decrease involume score relative to baseline], Progressive Disease [(PD)≥30%increase in volume relative to lowest score during the study whether atbaseline or some other visit] or Stable Disease [(SD) does not meet anyof the prior criteria based on score during study].

In addition to local review, all MRI scans will be centrally reviewed,and concordance between the local and central assessments of tumorresponse will be determined.

Duration of response will be calculated as the number of days from thefirst documentation of overall response (CR or PR) to the firstdocumentation of disease progression or death, whichever comes first.Patients who are alive and progression-free at the time of data analysiswill be censored at the time of their last assessment for tumorresponse.

In patients who respond adequately such that a decision is made toresect residual disease, the duration of response will be censored atthe time of the surgical procedure.

8.6. Safety Analyses

Safety analyses will be performed separately within both phases of thestudy and for all patients combined. Data from all patients that receiveany portion of at least 1 dose of FPA008 will be included in the safetyanalyses. AEs, clinical laboratory information, vital signs, ECOGperformance status, weight, ECGs, and concomitant medications/procedureswill be tabulated and summarized.

AEs will be summarized overall and with separate summaries for seriousAEs, AEs leading to discontinuation, AEs leading to death, and NCI CTCAEVersion 4.03 Grade 3 or higher AEs.

Weight and vital signs will be summarized descriptively (N, mean,standard deviation, median, minimum, and maximum). ECOG performancestatus will be summarized categorically and descriptively.

Shift tables displaying patient counts and percentages classified bybaseline grade and maximum grade on treatment will be provided forlaboratory data by cohort and overall. A marked laboratory change isdefined as a shift from a baseline Grade 0 to Grade 3 (non-hematologic)or Grade 4 (hematologic) on treatment, or a shift from a baseline Grade1 to Grade 4 on treatment. The number and percentage of patients withmarked laboratory changes will be tabulated by cohort and overall.

8.7. Efficacy Analysis

Efficacy analyses will be descriptive. The overall response rate will besummarized with frequencies and percentages. The duration of responsefor CR and PR patients will be summarized with descriptive statistics(N, arithmetic mean, standard deviation, median, minimum, and maximum)as well as categorically. Response and duration of response will bedetermined using RECIST 1.1. Kaplan-Meier methodology will be used tosummarize duration of response and PFS.

8.8. Pharmacokinetic Analyses

Individual and mean (±SD) serum FPA008 concentration-time data will betabulated and plotted by dose level. FPA008 PK parameters will becalculated from the serum drug concentration-time data using anon-compartmental analysis (NCA) method with intravenous infusion inputin Phoenix WinNonLin (Certara LP, St. Louis, Mo.). Alternative methodsmay be considered. Estimated individual and mean (±SD) PK parameterswill be tabulated and summarized by dose level. Other descriptivestatistics might be reported for serum FPA008 concentration-time dataand estimated PK parameters. Dose proportionality, drug accumulation,and attainment of steady state will be evaluated whenever it ispossible.

The impact of immunogenicity on FPA008 exposure will be assessed.

8.9. Interim Analyses

No formal interim analysis is planned.

Safety data will be reviewed on a routine basis by the Sponsor and CRO.In Phase 1, the Sponsor (and/or designee) and Investigator(s) willreview safety data from each dose cohort prior to dose escalation orde-escalation. Adverse event data from the extended treatment periodwill be presented to the medical monitors when available.

8.10. Determination of Sample Size

Three patients per dose group, with a sample size increase to 6 in thecase of DLT, is generally accepted as adequate to determine the safetyof escalating doses of novel oncologic drugs. If a DLT is observed in 1of 3 patients, then 3 additional patients will be enrolled at that samedose level. Dose escalation will continue until 2 of 3-6 patientstreated at a dose level experience a DLT. The MTD is defined as themaximum dose at which <33% of patients experience a DLT during Cycle 1.After the MTD is determined, additional patients may be recruited atthat dose level to further characterize the safety, PK, PD, andpreliminary efficacy of FPA008. It is anticipated that 12-15 patientsmay be enrolled in Phase 1.

For the objective of estimating the ORR of FPA008 in patients withPVNS/dt-TGCT, it is estimated that approximately 30 patients will beenrolled in Phase 2. In addition, a total of approximately 33 to 36patients will be enrolled at the RD overall. The following Table 6displays the corresponding 95% CI and the precision for various samplesizes and observed response rates (Agresti, 1998).

TABLE 6 Probability of Responders Precision Observed (longest SampleResponse one-sided Size Rate 95% CI CI length) 30 15/30 (50%) 33.2% to66.9% ~17% 16/30 (53%) 36.1% to 69.8% ~17% 17/30 (57%) 39.2% to 72.6%~18% 18/30 (60%) 42.3% to 75.4% ~18% 19/30 (63%) 45.5% to 78.2% ~17%20/30 (67%) 48.7% to 80.9% ~18% 21/30 (70%) 52.0% to 83.5% ~18% 22/30(73%) 55.4% to 86.0% ~18% 23/30 (77%) 58.8% to 88.5% ~18% 24/30 (80%)62.3% to 90.9% ~18% 35 17/35 (49%) 33.0% to 64.4% ~16% 18/35 (51%) 35.6%to 67.0% ~16% 19/35 (54%) 38.2% to 69.5% ~16% 20/35 (57%) 40.8% to 72.0%~16% 21/35 (60%) 43.5% to 74.5% ~16% 22/35 (63%) 46.3% to 76.9% ~17%23/35 (66%) 49.1% to 79.2% ~17% 24/35 (69%) 51.9% to 81.6% ~17% 25/35(71%) 54.8% to 83.8% ~16% 26/35 (74%) 57.8% to 86.0% ~16% 27/35 (77%)60.7% to 88.2% ~16% 28/35 (80%) 63.8% to 90.3% ~16% 40 20/40 (50%) 35.2%to 64.8% ~15% 21/40 (53%) 37.5% to 67.1% ~15% 22/40 (55%) 39.8% to 69.3%~15% 23/40 (58%) 42.2% to 71.5% ~16% 24/40 (60%) 44.6% to 73.7% ~15%25/40 (63%) 47.0% to 75.8% ~16% 26/40 (65%) 49.5% to 77.9% ~16% 27/40(68%) 51.9% to 80.0% ~16% 28/40 (70%) 54.5% to 82.0% ~16% 29/40 (73%)57.0% to 84.0% ~16% 30/40 (75%) 59.6% to 86.0% ~16% 31/40 (78%) 62.3% to87.9% ~16% 32/40 (80%) 65.0% to 89.8% ~15%

REFERENCES

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LIST OF ABBREVIATIONS AND DEFINITIONS

ADA Anti-drug antibodyADCC Antibody-dependent cell-mediated cytotoxicityAE Adverse eventALT Alanine transaminaseANC Absolute neutrophil countANOVA Analysis of varianceAST Aspartate transaminaseAUC Area under serum concentration-time curveβ-HCG Beta-human chorionic gonadotropinBUN Blood urea nitrogenCBC Complete blood countCK Creatinine kinaseC_(max) Maximum serum concentrationC_(min) Minimum serum concentration

CL Clearance

CO₂ Carbon dioxide (bicarbonate)CR Complete response

CRC Cohort Review Committee

CRO Clinician reported outcomeCRO Contract research organizationCSF1 Colony stimulating factor-1CT Computed tomographyCTx Collagen-type I C-terminal telopeptide

CTCAE Common Terminology Criteria for Adverse Events

DLT Dose-limiting toxicitydt-TGCT Diffuse type tenosynovial giant cell tumoreCRF Electronic case report form

ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group FDA Foodand Drug Administration

FNA Fine needle aspiration

GCP Good Clinical Practice GLP Good Laboratory Practice

HIV Human immunodeficiency virus

IB Investigator's Brochure

ICF Informed consent form

ICH International Conference on Harmonization IEC Independent EthicsCommittee IHC Immunohistochemistry

IND Investigational New Drug (application)INR International normalized ratio

IRB Institutional Review Board IV Intravenous

LDH Lactate dehydrogenaseLVEF Left ventricular ejection fractionMCH Mean corpuscular haemoglobinMCHC Mean corpuscular hemoglobin concentrationMCV Mean corpuscular volumeMRI Magnetic resonance imagingMTD Maximum tolerated dose

NCI National Cancer Institute

NOAEL No observed adverse effect levelNTX N-terminal telopeptide

NYHA New York Heart Association

ORR Objective response ratePD Progressive disease

PD Pharmacodynamic

PET Positron emission tomographyPFS Progression free survival

PK Pharmacokinetic

PR Partial responsePRO Patient reported outcomePS Performance statusPT Prothrombin timePTT Partial thromboplastin timePVNS Pigmented villonodular synovitisQTc Corrected QT intervalRBC Red blood cellRD Recommended dose

RECIST Response Evaluation Criteria in Solid Tumors

SAE Serious adverse eventSAP Statistical analysis planSD Stable diseaset_(1/2) Half-life

TB Tuberculosis

TRAP5b Tartrate resistant acid phosphatase 5bTVS Tumor volume scoreULN Upper limit of normalV_(ss) Volume of distribution at steady stateWBC White blood cell

APPENDIX 1 Schedule of Assessments Phases 1 and 2: Phase 1 ExtendedTreatment End of Long- Screening Cycle 1 Period/Phase 2 Cycle 2 andTreatment Term Day −28 to Day 8 Day 15 Subsequent Cycles Follow- FollowDay 0 Day 1 Day 2 Week Week Day 1 Day 15 up Up Procedure^(a,b) Week 0Week 1 2 3 ≥Week 4 Period^(s) Period^(t) Informed Consent xReview/Confirm Eligibility x x Criteria Medical History/Demographics x xPhysical Examination^(c) x x x Height and Weight^(d) x x x x x VitalSigns^(e) x x x x x x x ECOG Performance Status x x x x ScreeningLabs^(f) x Clinical Safety Labs^(g) x x x x x x x x 12-Lead ECG^(h) x xx x MRI of Involved Joint(s)^(i) x x x x Serum Pregnancy Test^(j) x x xOgilvie-Harris/EQ-5D-5L x x x x x Assessments^(k) Optional ArchivalTumor Tissue^(l) x Optional Synovial Biopsy^(m) x x Optional SynovialFluid x x Sampling^(n) ADA Sampling^(o) x x x x x PK and SerumBiomarkers x x x x x x x Sampling^(o) CD 14⁺/16⁺ Monocyte Sampling^(p) xx x x x x x Antinuclear Antibody (ANA)^(q) x x FPA008 Study Drug x x x xAdministration^(r) Adverse events x . . . x x x^(t) Prior/Concomitant x. . . x x x^(u) Medications Notes for Schedule of Assessments ^(a)Unlessspecified, procedure is to be completed within ± 72 hours of scheduledtime point and to be synchronized with administration day of FPA008infusion. ^(b)Any clinical assessment, laboratory study, or additionalnon-specified tests may be obtained at any time, if clinicallyindicated. ^(c)Complete physical examination will be performed atScreening, Day 1 of Cycle 2, 4, 6, at the 30 days (±7 days) End ofTreatment Follow-up Visit, and as determined by the Investigator,particularly to follow physical findings to resolution. Targetedphysical exams should be conducted at any time to follow up on AEreports. ^(d)Height is only required to be recorded at Screening. Weightis to be recorded Cycle 1, Days 1 and 15, and on Day 1 of subsequentcycles and at the End of Treatment Follow-up Visits. ^(e)Vital signsinclude pulse, blood pressure, respiration rate, and temperature in thesitting position. Measure prior to dose and after completion of the IVinfusion at the following time points: 5 minutes, 15 minutes, 30minutes, and 1 h post-dose. ^(f)Screening labs to include theQuantiferon test (for latent TB), and all women of childbearingpotential (including those who have had a tubal ligation < 6 months offirst dose of FPA008) will have a serum pregnancy test. ^(g)ClinicalSafety Labs (Table 5): Hematology including CBC with differential,platelets, hemoglobin, hematocrit, RBC, and RBC indices. Chemistryincludes CK (creatine kinase), AST (aspartate transaminase), ALT(alanine transaminase), troponins (cardiac and skeletal), CK isoenzymes,carbon dioxide, bilirubin (direct and total), BUN (blood urea nitrogen),calcium, chloride, creatinine, glucose, LDH (lactate dehydrogenase),phosphate, potassium, sodium, magnesium, and, if applicable, serumpregnancy. Additional tests may be obtained at any time, if clinicallyindicated. Urinalysis will only be done at Screening and at the End ofTreatment Follow-up Visits, and may be repeated at any time ifclinically indicated. Coagulation including INR, PTT and APTT.^(h)Obtain ECG records at Screening, approximately 30 minutes post-doseon Day 15 for all cycles, and at the 30 days (±7 days) End of TreatmentFollow-up Visit. Additional ECGs should be obtained at any time, and/orif serum CK or cardiac troponin is elevated; if abnormal (excludingsinus tachycardia), ECGs should be obtained (if clinically indicated),until the abnormality is resolved or clinically stable. ECGs for eachpatient should be obtained from the same machine whenever possible. Tominimize variability, it is important that patients be in a restingposition for approximately ≥ 5 minutes prior to each ECG evaluation.Body position should be consistently maintained for each ECG evaluationto prevent changes in heart rate. Environmental distractions (e.g.,television, radio, conversation) should be avoided during the pre-ECGresting period and during ECG recording. ^(i)MRI of the affectedjoint(s) will be performed during Screening and within 7 days of thefollowing: 4 (C2D1), 8 (C3D1), and 16 (C5D1) weeks. Patients should havean MRI done at the 30 days (±7 days) and 90 days (±7 days) End ofTreatment Follow-up Visits, unless it was already performed within theprevious 6 weeks or if tumor progression was previously determined.Patients who have not progressed and enter Long-Term Follow-up shouldhave MRI performed every 14 weeks (±2 weeks) for duration of responseuntil progression, the patient undergoes local therapy (e.g., resection,radiation) or a new systemic therapy is initiated, for up to 52 weeksfollowing C1D1. Response per MRI will be assessed using RECIST 1.1 andTVS based on independent central radiology review. ^(j)All women ofchildbearing potential (including those who have had a tubal ligation <6 months of first dose of FPA008) will have a serum pregnancy test atScreening and at End of Treatment Follow-up Visits. ^(k)TheOgilvie-Harris and EQ-5D-5L assessments will be performed at Screening,C1D15 (pre-dose), C2D1 (pre-dose), and then on Day 1 (pre-dose) for allsubsequent cycles through 24 weeks, or until treatment is discontinued.These can be omitted if performed within 6 weeks prior to the End ofTreatment Follow-up Visits. Patients who have not progressed and enterLong-Term Follow-up are to be followed every 14 weeks (±2 weeks) untilprogression, the patient undergoes local therapy (e.g., resection,radiation) or a new systemic therapy is initiated, for up to 52 weeksfollowing C1D1. ^(l)Optional archival tumor tissue will be collected atScreening, if available. ^(m)Optional synovial biopsies will becollected at Screening and up to −2 days prior to the C2D1 doseadministration. ^(n)Optional synovial fluid aspirate will be extractedat Screening and up to −2 days prior to the C2D1 dose administration.^(o)Blood samples will be collected for PK, ADA, and PD. Refer toAppendix 2 for collection times. ^(p)Whole blood will be collected andshipped overnight to the testing facility for analysis of CD14⁺/16⁺monocytes. Refer to Appendix 2 for collection times. ^(q)ANA testingwill be performed at Screening and at the 30 days (±7 days) End ofTreatment Follow-up Visit. ^(r)FPA008 study drug will be administeredevery 2 weeks (±3 days) in 28-day cycles for 24 weeks. The Cycle 2, Day1 infusion of FPA008 can only be administered after completion of the28-day DLT window. All subsequent infusions can be administered with a ±3 day window. Patients should not have 2 doses of FPA008 within 7 days.The first dose of each cycle is considered Day 1 of each cycle, cycleswill repeat every 28 days unless there is a treatment delay. Patientscan have treatment delay of Day 1 of the subsequent cycle as long as theDay 1 treatment is within weeks of the last treatment. FPA008 will beadministered over approximately 30 minutes. ^(s)Performed at 30 days (±7days), 60 days (±7 days) and 90 days (±7 days) after the last dose ofstudy treatment for all patients who complete the treatment period orwho terminate early. All adverse events (including serious adverseevents), regardless of attribution, will be recorded until 90 days afterthe last dose of study treatment. Ongoing adverse events will befollowed until the event has resolved to baseline grade, the event isassessed by the Investigator as stable, there is a satisfactoryexplanation for the changes observed, the patient is lost to follow-up,or the patient withdraws consent. ^(t)Patients who have not progressedshould continue onto Long-Term Follow-up after completing theEnd-of-Treatment Follow-up Period. Patients are to be followed every 14weeks (±2 weeks) until progression, the patient undergoes local therapy(e.g., resection, radiation) or a new systemic therapy is initiated, forup to 52 weeks following C1D1. ^(u)Only ongoing adverse events thoughtto be related to study treatment should be followed during the Long-TermFollow-up Period. ^(v)Only local therapy (e.g., resection, radiation) ora new systemic therapy will be recorded during the Long-Term Follow-upPeriod.

APPENDIX 2 Study Flowchart for Pharmacokinetic, Immunogenicity, andPharmacodynamic Blood Sample Collections Study Cycle Study Day TimePoint Type of Sample Cycle 1 Day 1 ≤4 hours Prior to infusion FPA008 PK(serum) (First Dose) ADA (serum) Serum Biomarkers (serum) CD14⁺/CD16⁺(whole blood) 15 minutes after end of FPA008 PK (serum) infusion (± 5minutes) Serum Biomarkers (serum) 4 hours after end of infusion FPA008PK (serum) (± 5 minutes) Serum Biomarkers (serum) CD14⁺/CD16⁺ (wholeblood) Day 2 24 hours after infusion FPA008 PK (serum) (± 2 hours) SerumBiomarkers (serum) CD14⁺/CD16⁺ (whole blood) Day 8 168 hours afterinfusion FPA008 PK (serum) (± 24 hours) Serum Biomarkers (serum)CD14⁺/CD16⁺ (whole blood) Day 15 ≤4 hours Prior to infusion FPA008 PK(serum) (Second Dose) ADA (serum) Serum Biomarkers (serum) CD14⁺/CD16⁺(whole blood) 15 minutes after end of FPA008 PK (serum) infusion (± 5minutes) Cycle 2 Day 1 ≤4 hours Prior to infusion FPA008 PK (serum)(First Dose) ADA (serum) Serum Biomarkers (serum) CD14⁺/CD16⁺ (wholeblood) Cycle 3, and Day 1 ≤4 hours Prior to infusion FPA008 PK (serum)5* (First Dose) ADA (serum) Serum Biomarkers (serum) CD14⁺/CD16⁺ (wholeblood) 15 minutes after end of FPA008 PK (serum) infusion (± 5 minutes)End of Not applicable Not applicable FPA008 PK (serum) Treatment ADA(serum) Follow- Serum Biomarkers (serum) upand Long- CD14⁺/CD16⁺ (wholeblood) Term Follow Up *The 15-minute post infusion PK blood draw is notrequired if FPA008 is not administered.

APPENDIX 3 ECOG Performance Status Grade Performance Status Criteria 0Fully active, able to carry on all pre-disease activities withoutrestriction. 1 Restricted in physically strenuous activity butambulatory and able to carry out work of a light sedentary nature (lighthousework, office work). 2 Ambulatory and capable of all self-care butunable to carry out any work activities. Up and about more than 50% ofwaking hours. 3 Capable of only limited self-care, confined to bed orchair more than 50% of waking hours. 4 Completely disabled. Cannot carryon any self-care. Totally confined to bed or chair.

Appendix 6: Management of Systemic Hypersensitivity Reactions

Staff administering study drug are required to closely monitor allpatients for possible systemic hypersensitivity reactions (e.g.,generalized exanthema, urticaria, paraesthesia, bronchoconstriction,palpitations) over the first 180 minutes after infusion, payingparticular attention to those patients with a history of asthma orsystemic reactions to allergenic injections.

All systemic hypersensitivity manifestations will be captured on theappropriate eCRF page(s) and identified as being due to ahypersensitivity reaction.

Systemic hypersensitivity reactions will be managed according totreatment protocols in effect at the investigational site. In theabsence of such a protocol, the following standardized treatmentprotocol will be used:

-   -   Clinically mild reactions (e.g., generalized rash or itching,        hives) are treated as soon as possible with Benadryl®        (diphenhydramine hydrochloride) 25 to 50 mg, orally or IV at the        Investigator's discretion. The period of observation is extended        beyond 3 hours, as necessary, until symptoms and signs have        resolved or stabilized. Patients who have experienced a        clinically mild reaction may continue to have study drug        administered.    -   Clinically moderate reactions (e.g., hypotension, shortness of        breath, facial edema) are treated immediately and supportive        care measures instituted as medically indicated (e.g., IV        fluids, corticosteroids, vasopressors, oxygen, bronchodilators,        diphenhydramine, and acetaminophen). Vital signs are monitored        at 10-minute intervals until they have normalized. The period of        observation is extended beyond 3 hours, if necessary, until        symptoms and signs have resolved. In the event of a clinically        moderate reaction, the patient should receive no further        treatment with study drug.    -   Clinically severe reactions (e.g., marked hypotension, syncope,        severe bronchoconstriction, tongue or throat swelling,        significant angioedema) are treated immediately, under the        direct supervision of the investigator, and supportive care        measures instituted as medically indicated (e.g., IV fluids,        corticosteroids, vasopressors, oxygen, bronchodilators,        diphenhydramine, and acetaminophen). Vital signs and systems are        monitored at a minimum of 10-minute intervals for as long as the        investigator considers it necessary to ensure patient safety. In        the event of a clinically severe reaction, the patient should        receive no further treatment with study drug.

These clinical classifications are for the purpose of recommendingtreatment for patients who experience systemic hypersensitivityreactions. These classifications will not be used to grade the severityof the systemic hypersensitivity event within the eCRF. The severity ofthese events will be documented per the grading system presented in NCICTCAE v4.03.

Preliminary data from this trial shows that pateints under treatmentwith a dose as low as 1 mg/kg demonstrated clinical improvement in someparameters according to the Ogilive-Harris Score for PVNS, including:

-   -   1) reducing pain, for example, from severe (0 points) to none (3        points),    -   2) enhancing range of motion, for example, from loss more than        20% to no loss, and    -   3) increasing functional capacity, for example, from capable of        having some activity to capable of have all activity.

An improving effect of the treatment was also seen with EQ-5D-5LEvaluation as least some of the patients receiving the treatment hadimproved ability in washing and dressing and other self-care activity.

Table of Sequences

Table 5 provides certain sequences discussed herein. All polypeptide andantibody sequences are shown without leader sequences, unless otherwiseindicated.

TABLE 5 Sequences and Descriptions SEQ ID NO Description Sequence  1hCSFER IPVIEPSVPE LVVKPGATVT LRCVGNGSVE WDGPPSPHWT LYSDGSSSIL(full-length STNNATFQNT GTYRCTEPGD PLGGSAAIHL YVKDPARPWN VLAQEVVVFEno leader DQDALLPCLL TDPVLEAGVS LVRVRGRPLM RHTNYSFSPW HGFTIHRAKFsequence) IQSQDYQCSA LMGGRKVMSI SIRLKVQKVI PGPPALTLVP AELVRIRGEAAQIVCSASSV DVNFDVFLQH NNTKLAIPQQ SDFHNNRYQK VLTLNLDQVDFQHAGNYSCV ASNVQGKHST SMFFRVVESA YLNLSSEQNL IQEVTVGEGLNLKVMVEAYP GLQGFNWTYL GPFSDHQPEP KLANATTKDT YRHTFTLSLPRLKPSEAGRY SFLARNPGGW RALTFELTLR YPPEVSVIWT FINGSGTLLCAASGYPQPNV TWLQCSGHTD RCDEAQVLQV WDDPYPEVLS QEPFHKVTVQSLLTVETLEH NQTYECRAHN SVGSGSWAFI PISAGAHTHP PDEFLFTPVVVACMSIMALL LLLLLLLLYK YKQKPKYQVR WKIIESYEGN SYTFIDPTQLPYNEKWEFPR NNLQFGKTLG AGAFGKVVEA TAFGLGKEDA VLKVAVKMLKSTAHADEKEA LMSELKIMSH LGQHENIVNL LGACTHGGPV LVITEYCCYGDLLNFLRRKA EAMLGPSLSP GQDPEGGVDY KNIHLEKKYV RRDSGFSSQGVDTYVEMRPV STSSNDSFSE QDLDKEDGRP LELRDLLHFS SQVAQGMAFLASKNCIHRDV AARNVLLTNG HVAKIGDFGL ARDIMNDSNY IVKGNARLPVKWMAPESIFD CVYTVQSDVW SYGILLWEIF SLGLNPYPGI LVNSKFYKLVKDGYQMAQPA FAPKNIYSIM QACWALEPTH RPTFQQICSF LQEQAQEDRRERDYTNLPSS SRSGGSGSSS SELEEESSSE HLTCCEQGDI AQPLLQPNNY QFC  2 hCSFERMGPGVLLLLL VATAWHGQGI PVIEPSVPEL VVKPGATVTL RCVGNGSVEW (full-length,DGPPSPHWTL YSDGSSSILS TNNATFQNTG TYRCTEPGDP LGGSAAIHLY + leaderVKDPARPWNV LAQEVVVFED QDALLPCLLT DPVLEAGVSL VRVRGRPLMR sequence)HTNYSFSPWH GFTIHRAKFI QSQDYQCSAL MGGRKVMSIS IRLKVQKVIPGPPALTLVPA ELVRIRGEAA QIVCSASSVD VNFDVFLQHN NTKLAIPQQSDFHNNRYQKV LTLNLDQVDF QHAGNYSCVA SNVQGKHSTS MFFRVVESAYLNLSSEQNLI QEVTVGEGLN LKVMVEAYPG LQGFNWTYLG PFSDHQPEPKLANATTKDTY RHTFTLSLPR LKPSEAGRYS FLARNPGGWR ALTFELTLRYPPEVSVIWTF INGSGTLLCA ASGYPQPNVT WLQCSGHTDR CDEAQVLQVWDDPYPEVLSQ EPFHKVTVQS LLTVETLEHN QTYECRAHNS VGSGSWAFIPISAGAHTHPP DEFLFTPVVV ACMSIMALLL LLLLLLLYKY KQKPKYQVRWKIIESYEGNS YTFIDPTQLP YNEKWEFPRN NLQFGKTLGA GAFGKVVEATAFGLGKEDAV LKVAVKMLKS TAHADEKEAL MSELKIMSHL GQHENIVNLLGACTHGGPVL VITEYCCYGD LLNFLRRKAE AMLGPSLSPG QDPEGGVDYKNIHLEKKYVR RDSGFSSQGV DTYVEMRPVS TSSNDSFSEQ DLDKEDGRPLELRDLLHFSS QVAQGMAFLA SKNCIHRDVA ARNVLLTNGH VAKIGDFGLARDIMNDSNYI VKGNARLPVK WMAPESIFDC VYTVQSDVWS YGILLWEIFSLGLNPYPGIL VNSKFYKLVK DGYQMAQPAF APKNIYSIMQ ACWALEPTHRPTFQQICSFL QEQAQEDRRE RDYTNLPSSS RSGGSGSSSS ELEEESSSEHLTCCEQGDIA QPLLQPNNYQ FC  5 hCSFERIPVIEPSVPE LVVKPGATVT LRCVGNGSVE WDGPPSPHWT LYSDGSSSIL ECD.506STNNATFQNT GTYRCTEPGD PLGGSAAIHL YVKDPARPWN VLAQEVVVFEDQDALLPCLL TDPVLEAGVS LVRVRGRPLM RHTNYSFSPW HGFTIHRAKFIQSQDYQCSA LMGGRKVMSI SIRLKVQKVI PGPPALTLVP AELVRIRGEAAQIVCSASSV DVNFDVFLQH NNTKLAIPQQ SDFHNNRYQK VLTLNLDQVDFQHAGNYSCV ASNVQGKHST SMFFRVVESA YLNLSSEQNL IQEVTVGEGLNLKVMVEAYP GLQGFNWTYL GPFSDHQPEP KLANATTKDT YRHTFTLSLPRLKPSEAGRY SFLARNPGGW RALTFELTLR YPPEVSVIWT FINGSGTLLCAASGYPQPNV TWLQCSGHTD RCDEAQVLQV WDDPYPEVLS QEPFHKVTVQSLLTVETLEH NQTYECRAHN SVGSGSWAFI PISAGAH  6 hCSFERIPVIEPSVPE LVVKPGATVT LRCVGNGSVE WDGPPSPHWT LYSDGSSSIL ECD.506-FcSTNNATFQNT GTYRCTEPGD PLGGSAAIHL YVKDPARPWN VLAQEVVVFEDQDALLPCLL TDPVLEAGVS LVRVRGRPLM RHTNYSFSPW HGFTIHRAKFIQSQDYQCSA LMGGRKVMSI SIRLKVQKVI PGPPALTLVP AELVRIRGEAAQIVCSASSV DVNFDVFLQH NNTKLAIPQQ SDFHNNRYQK VLTLNLDQVDFQHAGNYSCV ASNVQGKHST SMFFRVVESA YLNLSSEQNL IQEVTVGEGLNLKVMVEAYP GLQGFNWTYL GPFSDHQPEP KLANATTKDT YRHTFTLSLPRLKPSEAGRY SFLARNPGGW RALTFELTLR YPPEVSVIWT FINGSGTLLCAASGYPQPNV TWLQCSGHTD RCDEAQVLQV WDDPYPEVLS QEPFHKVTVQSLLTVETLEH NQTYECRAHN SVGSGSWAFI PISAGAHEPK SSDKTHTCPPCPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWYVDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKALPAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIAVEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVMHEALHNHYTQ KSLSLSPGK  7 cyroCSF1RMGPGVLLLLL VVTAWHGQGI PVIEPSGPEL VVKPGETVTL RCVGNGSVEW ECD (withDGPISPHWTL YSDGPSSVLT TTNATFQNTR TYRCTEPGDP LGGSAAIHLY leaderVKDPARPWNV LAKEVVVFED QDALLPCLLT DPVLEAGVSL VRLRGRPLLR sequence)HTNYSFSPWH GFTIHRAKFI QGQDYQCSAL MGSRKVMSIS IRLKVQKVIPGPPALTLVPA ELVRIRGEAA QIVCSASNID VDFDVFLQHN TTKLAIPQRSDFHDNRYQKV LTLSLGQVDF QHAGNYSCVA SNVQGKHSTS MFFRVVESAYLDLSSEQNLI QEVTVGEGLN LKVMVEAYPG LQGFNWTYLG PFSDHQPEPKLANATTKDTY RHTFTLSLPR LKPSEAGRYS FLARNPGGWR ALTFELTLRYPPEVSVIWTS INGSGTLLCA ASGYPQPNVT WLQCAGHTDR CDEAQVLQVWVDPHPEVLSQ EPFQKVTVQS LLTAETLEHN QTYECRAHNS VGSGSWAFIP ISAGAR  8cyroCSF1R MGPGVLLLLL VVTAWHGQGI PVIEPSGPEL VVKPGETVTL RCVGNGSVEW ECD-FcDGPISPHWTL YSDGPSSVLT TTNATFQNTR TYRCTEPGDP LGGSAAIHLY (with leaderVKDPARPWNV LAKEVVVFED QDALLPCLLT DPVLEAGVSL VRLRGRPLLR sequence)HTNYSFSPWH GFTIHRAKFI QGQDYQCSAL MGSRKVMSIS IRLKVQKVIPGPPALTLVPA ELVRIRGEAA QIVCSASNID VDFDVFLQHN TTKLAIPQRSDFHDNRYQKV LTLSLGQVDF QHAGNYSCVA SNVQGKHSTS MFFRVVESAYLDLSSEQNLI QEVTVGEGLN LKVMVEAYPG LQGFNWTYLG PFSDHQPEPKLANATTKDTY RHTFTLSLPR LKPSEAGRYS FLARNPGGWR ALTFELTLRYPPEVSVIWTS INGSGTLLCA ASGYPQPNVT WLQCAGHTDR CDEAQVLQVWVDPHPEVLSQ EPFQKVTVQS LLTAETLEHN QTYECRAHNS VGSGSWAFIPISAGARGSEP KSSDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTPEVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLTVLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDELTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLYSKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK  3 Light chainMETDTLLLWV LLLWVPGSTG leader sequence  4 Heavy chainMAVLGLLLCL VTFPSCVLS leader sequence  9 Fab 0301EVQLQQSGPE LVRPGASVKM SCKASGYTFT DNYMIWVKQS HGKSLEWIGD heavyINPYNGGTTF NQKFKGKATL TVEKSSSTAY MQLNSLTSED SAVYYCARES variablePYFSNLYVMD YWGQGTSVTV SS region 10 Fab 0301NIVLTQSPAS LAVSLGQRAT ISCKASQSVD YDGDNYMNWY QQKPGQPPKL light chainLIYAASNLES GIPARFSGSG SGTDFTLNIH PVEEEDAATY YCHLSNEDLS variableTFGGGTKLEI K region 11 Fab 0302EIQLQQSGPE LVKPGASVKM SCKASGYTFS DFNIHWVKQK PGQGLEWIGY heavy chainINPYTDVTVY NEKFKGKATL TSDRSSSTAY MDLSSLTSED SAVYYCASYF variableDGTFDYALDY WGQGTSITVS s region 12 Fab 0302DVVVTQTPAS LAVSLGQRAT ISCRASESVD NYGLSFMNWF QQKPGQPPKL light chainLIYTASNLES GIPARFSGGG SRTDFTLTID PVEADDAATY FCQQSKELPW variableTFGGGTRLEI K region 13 Fab 0311EIQLQQSGPD LMKPGASVKM SCKASGYIFT DYNMHWVKQN QGKSLEWMGE heavy chainINPNNGVVVY NQKFKGTTTL TVDKSSSTAY MDLHSLTSED SAVYYCTRAL variableYHSNFGWYFD SWGKGTTLTV SS region 14 Fab 0311DIVLTQSPAS LAVSLGQRAT ISCKASQSVD YDGDSHMNWY QQKPGQPPKL light chainLIYTASNLES GIPARFSGSG SGADFTLTIH PVEEEDAATY YCQQGNEDPW variableTFGGGTRLEI K region 15 0301 heavy GYTFTDNYMI chain CDR1 16 0301 heavyDINPYNGGTT FNQKFKG chain CDR2 17 0301 heavy ESPYFSNLYV MDY chain CDR3 180301 light KASQSVDYDG DNYMN chain CDR1 19 0301 light AASNLES chain CDR220 0301 light HLSNEDLST chain CDR3 21 0302 heavy GYTFSDFNIH chain CDR122 0302 heavy YINPYTDVTV YNEKFKG chain CDR2 23 0302 heavy YFDGTFDYAL DYchain CDR3 24 0302 light RASESVDNYG LSFMN chain CDR1 25 0302 lightTASNLES chain CDR2 26 0302 light QQSKELPWT chain CDR3 27 0311 heavyGYIFTDYNMH chain CDR1 28 0311 heavy EINPNNGVVV YNQKFKG chain CDR2 290311 heavy ALYHSNFGWY FDS chain CDR3 30 0311 light KASQSVDYDG DSHMNchain CDR1 31 0311 light TASNLES chain CDR2 32 0311 light QQGNEDPWTchainCDR3 33 cAb 0301EVQLQQSGPE LVRPGASVKM SCKASGYTFT DNYMIWVKQS HGKSLEWIGD heavy chainINPYNGGTTF NQKFKGKATL TVEKSSSTAY MQLNSLTSED SAVYYCARESPYFSNLYVMD YWGQGTSVTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 34 cAb 0301NIVLTQSPAS LAVSLGQRAT ISCKASQSVD YDGDNYMNWY QQKPGQPPKL light chainLIYAASNLES GIPARFSGSG SGTDFTLNIH PVEEEDAATY YCHLSNEDLSTFGGGTKLEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 35 cAb 0302EIQLQQSGPE LVKPGASVKM SCKASGYTFS DFNIHWVKQK PGQGLEWIGY heavy chainINPYTDVTVY NEKFKGKATL TSDRSSSTAY MDLSSLTSED SAVYYCASYFDGTFDYALDY WGQGTSITVS SASTKGPSVF PLAPCSRSTS ESTAALGCLVKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTKTYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEFLGGPS VFLFPPKPKDTLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNSTYRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVYTLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLDSDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK 36 cAb 0302DVVVTQTPAS LAVSLGQRAT ISCRASESVD NYGLSFMNWF QQKPGQPPKL light chainLIYTASNLES GIPARFSGGG SRTDFTLTID PVEADDAATY FCQQSKELPWTFGGGTRLEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 37 cAb 0311EIQLQQSGPD LMKPGASVKM SCKASGYIFT DYNMHWVKQN QGKSLEWMGE heavy chainINPNNGVVVY NQKFKGTTTL TVDKSSSTAY MDLHSLTSED SAVYYCTRALYHSNFGWYFD SWGKGTTLTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 38 cAb 0311DIVLTQSPAS LAVSLGQRAT ISCKASQSVD YDGDSHMNWY QQKPGQPPKL light chainLIYTASNLES GIPARFSGSG SGADFTLTIH PVEEEDAATY YCQQGNEDPWTFGGGTRLEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 39 h0301-H0QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DNYMIWVRQA PGQGLEWMGD heavy chainINPYNGGTTF NQKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARES variablePYFSNLYVMD YWGQGTLVTV SS region 40 h0301-H1QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DNYMIWVRQA PGQGLEWMGD heavy chainINPYNGGTTF NQKFKGRVTI TVDKSTSTAY MELSSLRSED TAVYYCARES variablePYFSNLYVMD YWGQGTLVTV SS region 41 h0301-H2QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DNYMIWVRQA PGQGLEWIGD heavy chainINPYNGGTTF NQKFKGRATL TVDKSTSTAY MELSSLRSED TAVYYCARES variablePYFSNLYVMD YWGQGTLVTV SS region 42 H0302-H1QVQLVQSGAE VKKPGSSVKV SCKASGYTFS DFNIHWVRQA PGQGLEWMGY heavy chainINPYTDVTVY NEKFKGRVTI TSDKSTSTAY MELSSLRSED TAVYYCASYF variableDGTFDYALDY WGQGTLVTVS s region 43 H0302-H2QVQLVQSGAE VKKPGSSVKV SCKASGYTFS DFNIHWVRQA PGQGLEWIGY heavy chainINPYTDVTVY NEKFKGRATL TSDKSTSTAY MELSSLRSED TAVYYCASYF variableDGTFDYALDY WGQGTLVTVS s region 44 H0311-H1QVQLVQSGAE VKKPGSSVKV SCKASGYIFT DYNMHWVRQA PGQGLEWMGE heavy chainINPNNGVVVY NQKFKGRVTI TVDKSTSTAY MELSSLRSED TAVYYCTRAL variableYHSNFGWYFD SWGQGTLVTV SS region 45 H0311-H2QVQLVQSGAE VKKPGSSVKV SCKASGYIFT DYNMHWVRQA PGQGLEWMGE heavy chainINPNNGVVVY NQKFKGTTTL TVDKSTSTAY MELSSLRSED TAVYYCTRAL variableYHSNFGWYFD SWGQGTLVTV SS region 46 h0301-L0EIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDNYMNWY QQKPGQAPRL light chainLIYAASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCHLSNEDLS variableTFGGGTKVEI K region 47 h0301-L1NIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDNYMNWY QQKPGQAPRL light chainLIYAASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCHLSNEDLS variableTFGGGTKVEI K region 48 H0302-L0EIVLTQSPAT LSLSPGERAT LSCRASESVD NYGLSFMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQQSKELPW variableTFGQGTKVEI K region 49 H0302-L1EIVLTQSPAT LSLSPGERAT LSCRASESVD NYGLSFMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SRTDFTLTIS SLEPEDFAVY YCQQSKELPW variableTFGQGTKVEI K region 50 H0302-L2EIVVTQSPAT LSLSPGERAT LSCRASESVD NYGLSFMNWF QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SRTDFTLTIS SLEPEDFAVY YCQQSKELPW variableTFGQGTKVEI K region 51 H0311-L0EIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDSHMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQQGNEDPW variableTFGQGTKVEI K region 52 H0311-L1DIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDSHMNWY QQKPGQAPRL heavy chainLIYTASNLES GIPARFSGSG SGADFTLTIS SLEPEDFAVY YCQQGNEDPW variableTFGQGTKVEI K region 53 h0301-H0QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DNYMIWVRQA PGQGLEWMGD heavy chainINPYNGGTTF NQKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARESPYFSNLYVMD YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 54 h0301-H1QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DNYMIWVRQA PGQGLEWMGD heavy chainINPYNGGTTF NQKFKGRVTI TVDKSTSTAY MELSSLRSED TAVYYCARESPYFSNLYVMD YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 55 h0301-H2QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DNYMIWVRQA PGQGLEWIGD heavy chainINPYNGGTTF NQKFKGRATL TVDKSTSTAY MELSSLRSED TAVYYCARESPYFSNLYVMD YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 56 H0302-H1QVQLVQSGAE VKKPGSSVKV SCKASGYTFS DFNIHWVRQA PGQGLEWMGY heavy chainINPYTDVTVY NEKFKGRVTI TSDKSTSTAY MELSSLRSED TAVYYCASYFDGTFDYALDY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLVKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTKTYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEFLGGPS VFLFPPKPKDTLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNSTYRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVYTLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLDSDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK 57 H0302-H2QVQLVQSGAE VKKPGSSVKV SCKASGYTFS DFNIHWVRQA PGQGLEWIGY heavy chainINPYTDVTVY NEKFKGRATL TSDKSTSTAY MELSSLRSED TAVYYCASYFDGTFDYALDY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLVKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTKTYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEFLGGPS VFLFPPKPKDTLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNSTYRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVYTLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLDSDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK 58 H0311-H1QVQLVQSGAE VKKPGSSVKV SCKASGYIFT DYNMHWVRQA PGQGLEWMGE heavy chainINPNNGVVVY NQKFKGRVTI TVDKSTSTAY MELSSLRSED TAVYYCTRALYHSNFGWYFD SWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 59 H0311-H2QVQLVQSGAE VKKPGSSVKV SCKASGYIFT DYNMHWVRQA PGQGLEWMGE heavy chainINPNNGVVVY NQKFKGTTTL TVDKSTSTAY MELSSLRSED TAVYYCTRALYHSNFGWYFD SWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCLVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGTKTYTCNVDHK PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPKDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNSTYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVLDSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 60 h0301-L0EIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDNYMNWY QQKPGQAPRL light chainLIYAASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCHLSNEDLSTFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 61 h0301-L1NIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDNYMNWY QQKPGQAPRL light chainLIYAASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCHLSNEDLSTFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 62 H0302-L0EIVLTQSPAT LSLSPGERAT LSCRASESVD NYGLSFMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQQSKELPWTFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 63 H0302-L1EIVLTQSPAT LSLSPGERAT LSCRASESVD NYGLSFMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SRTDFTLTIS SLEPEDFAVY YCQQSKELPWTFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 64 H0302-L2EIVVTQSPAT LSLSPGERAT LSCRASESVD NYGLSFMNWF QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SRTDFTLTIS SLEPEDFAVY YCQQSKELPWTFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 65 H0311-L0EIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDSHMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQQGNEDPWTFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 66 H0311-L1DIVLTQSPAT LSLSPGERAT LSCKASQSVD YDGDSHMNWY QQKPGQAPRL light chainLIYTASNLES GIPARFSGSG SGADFTLTIS SLEPEDFAVY YCQQGNEDPWTFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKVQWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEVTHQGLSSPVT KSFNRGEC 67 HumanEEVSEYCSHM IGSGHLQSLQ RLIDSQMETS CQITFEFVDQ EQLKDPVCYL CSF1KKAFLLVQDI MEDTMRFRDN TPNAIAIVQL QELSLRLKSC FTKDYEEHDKACVRTFYETP LQLLEKVKNV FNETKNLLDK DWNIFSKNCN NSFAECSSQG HERQSEGS 68Human IL- NEPLEMWPLT QNEECTVTGF LRDKLQYRSR LQYMKHYFPI NYKISVPYEG 34VFRIANVTRL QRAQVSEREL RYLWVLVSLSATESVQDVLL EGHPSWKYLQEVQTLLLNVQ QGLTDVEVSP KVESVLSLLN APGPNLKLVR PKALLDNCFRVMELLYCSCC KQSSVLNWQD CEVPSPQSCS PEPSLQYAAT QLYPPPPWSPSSPPHSTGSV RPVRAQGEGL LP 69 Human QVQLVQSGAE VKKPGSSVKV SCKAS acceptor AFR1 70 Human WVRQAPGQGL EWMG acceptor A FR2 71 HumanRVTITADKST STAYMELSSL RSEDTAVYYC AR acceptor A FR3 72 Human WGQGTLVTVS Sacceptor A FR4 73 Human QVQLVQSGAE VKKPGSSVKV SCKAS acceptor B FR1 74Human WVRQAPGQGL EWMG acceptor B FR2 75 HumanRVTITADKST STAYMELSSL RSEDTAVYYC AR acceptor B FR3 76 Human WGQGTLVTVSSacceptor B FR4 77 Human QVQLVQSGAE VKKPGSSVKV SCKAS acceptor C FR1 78Human WVRQAPGQGL EWMG acceptor C FR2 79 HumanRVTITADKST STAYMELSSL RSEDTAVYYC AR acceptor C FR3 80 Human WGQGTLVTVS Sacceptor C FR4 81 Human EIVLTQSPAT LSLSPGERAT LSC acceptor D FR1 82Human WYQQKPGQAP RLLIY acceptor D FR2 83 HumanGIPARFSGSG SGTDFTLTIS SLEPEDFAVY YC acceptor D FR3 84 Human FGGGTKVEIKacceptor D FR4 85 Human EIVLTQSPAT LSLSPGERAT LSC acceptor E FR1 86Human WYQQKPGQAP RLLIY acceptor E FR2 87 HumanGIPARFSGSG SGTDFTLTIS SLEPEDFAVY YC acceptor E  FR3 88 Human FGQGTKVEIKacceptor E FR4 89 Human EIVLTQSPAT LSLSPGERAT LSC acceptor F FR1 90Human WYQQKPGQAP RLLIY acceptor F FR2 91 HumanGIPARFSGSG SGTDFTLTIS SLEPEDFAVY YC acceptor F FR3 92 Human FGQGTKVEIKacceptor F FR4 93 mCSF1RAPVIEPSGPE LVVEPGETVT LRCVSNGSVE WDGPISPYWT LDPESPGSTL ECD-FcTTRNATFKNT GTYRCTELED PMAGSTTIHL YVKDPAHSWN LLAQEVTVVEGQEAVLPCLI TDPALKDSVS LMREGGRQVL RKTVYFFSPW RGFIIRKAKVLDSNTYVCKT MVNGRESTST GIWLKVNRVH PEPPQIKLEP SKLVRIRGEAAQIVCSATNA EVGFNVILKR GDTKLEIPLN SDFQDNYYKK VRALSLNAVDFQDAGIYSCV ASNDVGTRTA TMNFQVVESA YLNLTSEQSL LQEVSVGDSLILTVHADAYP SIQHYNWTYL GPFFEDQRKL EFITQRAIYR YTFKLFLNRVKASEAGQYFL MAQNKAGWNN LTFELTLRYP PEVSVTWMPV NGSDVLFCDVSGYPQPSVTW MECRGHTDRC DEAQALQVWN DTHPEVLSQK PFDKVIIQSQLPIGTLKHNM TYFCKTHNSV GNSSQYFRAV SLGQSKQEPK SSDKTHTCPPCPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWYVDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKALPAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIAVEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVMHEALHNHYTQ KSLSLSPGK 94 HumanASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV IgG4 S241PHTFPAVLQSS GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVESKYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSQEDPEVQFNWYVD GVEVHNAKTK PREEQFNSTY RVVSVLTVLH QDWLNGKEYKCKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVKGFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEGNVFSCSVMHE ALHNHYTQKS LSLSLGK 95 Human IgκRTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSGNSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

1. A method of treating a proliferative disorder involving a synovialjoint and/or tendon sheath in a subject, wherein the proliferativedisorder is selected from pigmented villonodular synovitis (PVNS), giantcell tumor of the tendon sheath (GCTTS), tenosynovial giant cell tumor(TGCT) such as diffuse type tenosynovial giant cell tumor (dtTGCT), andPVNS/dtTGCT, comprising administering to the subject a dose of 1-4 mg/kgof an antibody that binds human CSF1R.
 2. (canceled)
 3. A method oftreating pigmented villonodular synovitis (PVNS) in a subject comprisingadministering to the subject a dose of 1-4 mg/kg of an antibody thatbinds human CSF1R.
 4. The method of claim 1, wherein the antibody isadministered once per week, once per two weeks, once per three weeks, oronce per month.
 5. (canceled)
 6. The method of claim 3, wherein the PVNStumor volume is reduced by at least 30% or at least 40% or at least 50%or at least 60% or at least 70% after administration of at least two, atleast three, at least four, at least five, at least six, at least seven,at least eight, at least nine, or at least ten doses of the antibodythat binds CSF1R.
 7. The method of claim 6, wherein the tumor volume istumor volume in a single joint.
 8. The method of claim 7, wherein thesingle joint is selected from a hip joint and a knee joint.
 9. Themethod of claim 6, wherein the tumor volume is total tumor volume in alljoints affected by PVNS.
 10. The method of claim 1, wherein, prior toadministering the first dose of the antibody, the subject received afirst therapy selected from surgical synovectomy, radiation beamtherapy, radio isotope synovectomy, and joint replacement.
 11. Themethod of claim 10, wherein the disorder recurred or progressed afterthe first therapy.
 12. The method of claim 1, wherein the antibody isadministered prior to a therapy selected from surgical synovectomy,radiation beam therapy, radio isotope synovectomy, and jointreplacement, or wherein the tumor is unresectable.
 13. The method ofclaim 1, wherein the subject has not received prior treatment with aCSF1R inhibitor.
 14. The method of claim 1, wherein the anti-CSF1Rantibody blocks binding of CSF1 and/or IL-34 to CSF1R.
 15. The method ofclaim 1, wherein the anti-CSF1R antibody inhibits ligand-induced CSF1Rphosphorylation in vitro. 16.-39. (canceled)
 40. The method of claim 1,wherein the subject experiences at least one of (a) a reduction in jointpain, (b) an increase range of motion in a joint, and (c) an increase infunctional capacity of a joint, following at least one dose of theantibody.
 41. The method of claim 1, wherein the antibody isadministered once per two weeks.
 42. The method of claim 40, wherein theantibody is administered once per two weeks.
 43. The method of claim 1,wherein the antibody is administered at a dose of 1 or 2 mg/kg once pertwo weeks.
 44. The method of claim 40, wherein the antibody isadministered at a dose of 1 or 2 mg/kg once per two weeks.
 45. Themethod of claim 3, wherein the subject experiences at least one of (a) areduction in joint pain, (b) an increase range of motion in a joint, and(c) an increase in functional capacity of a joint, following at leastone dose of the antibody.
 46. The method of claim 3, wherein theantibody is administered once per two weeks.
 47. method of claim 45,wherein the antibody is administered once per two weeks.
 48. The methodof claim 3, wherein the antibody is administered at a dose of 1 or 2mg/kg once per two weeks.
 49. The method of claim 45, wherein theantibody is administered at a dose of 1 or 2 mg/kg once per two weeks.50. A method of reducing pain in a subject with pigmented villonodularsynovitis (PVNS), comprising administering to the subject a dose of 1-4mg/kg of an antibody that binds CSF1R, wherein the dose of the antibodyis capable of reducing pain in PVNS subjects independently of tumorresponse.
 51. The method of claim 50, wherein the antibody isadministered once per two weeks.
 52. The method of claim 50, wherein theantibody is administered at a dose of 1 or 2 mg/kg once per two weeks.